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@article{faucris.290418787,
abstract = {High dietary salt intake is associated with hypertension; the prevalence of salt-sensitive hypertension increases with age. We hypothesized that tissue Na might accumulate in hypertensive patients and that aging might be accompanied by Na deposition in tissue. We implemented Na magnetic resonance imaging to measure Na content of soft tissues in vivo earlier, but had not studied essential hypertension. We report on a cohort of 56 healthy control men and women, and 57 men and women with essential hypertension. The ages ranged from 22 to 90 years. Na magnetic resonance imaging measurements were made at the level of the calf. We observed age-dependent increases in Na content in muscle in men, whereas muscle Na content did not change with age in women. We estimated water content with conventional MRI and found no age-related increases in muscle water in men, despite remarkable Na accumulation, indicating water-free Na storage in muscle. With increasing age, there was Na deposition in the skin in both women and men; however, skin Na content remained lower in women. Similarly, this sex difference was found in skin water content, which was lower in women than in men. In contrast to muscle, increasing Na content was paralleled with increasing skin water content. When controlled for age, we found that patients with refractory hypertension had increased tissue Na content, compared with normotensive controls. These observations suggest that Na magnetic resonance imaging could have utility in assessing the role of tissue Na storage for cardiovascular morbidity and mortality in longitudinal studies. © 2013 American Heart Association, Inc.},
author = {Kopp, Christoph and Linz, Peter and Dahlmann, Anke and Hammon, Matthias and Jantsch, Jonathan and Mueller, Dominik N. and Schmieder, Roland and Cavallaro, Alexander Josef and Eckardt, Kai-Uwe and Uder, Michael and Luft, Friedrich C. and Titze, Jens},
doi = {10.1161/HYPERTENSIONAHA.111.00566},
faupublication = {yes},
journal = {Hypertension},
keywords = {aging; gender difference; hypertension; salt; sodium MRI},
note = {CRIS-Team Scopus Importer:2023-03-08},
pages = {635-640},
peerreviewed = {Yes},
title = {{23Na} magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients},
volume = {61},
year = {2013}
}
@article{faucris.109344444,
abstract = {Textbook theory holds that extracellular fluids readily equilibrate, electrolyte concentrations in the extracellular fluid compartments are constant, and the kidney is solely responsible for controlling the body sodium content.Investigation of salt and water balance traditionally relies on short-term studies of bodily responses to extremes in salt intake. Ultra-long-term sodium balance studies instead studied the kidney's response to constant salt intake. The studies suggest that steady-state sodium balance in humans is characterized by storage and release of sodium from the body. The absence of accompanying changes in the body fluid matrix indicates the presence of metabolically relevant sodium reservoir sites in the body. In rats and mice, sodium is stored in skeletal muscle and skin. Homeostatic immune cells control reservoir electrolyte metabolism via the lymphatics. Failure of this extrarenal clearance process results in skin electrolyte accumulation and arterial hypertension. Noninvasive detection of sodium reservoir metabolism in patients by NaMRi methodology allows rapid transfer into the clinical arena.Body sodium content in humans and animals is not constant, does not always readily equilibrate with water, and is not exclusively controlled by the kidneys. This different view provides with new research avenues for basic and clinical investigators.},
author = {Titze, Jens},
doi = {10.1097/MNH.0000000000000085},
faupublication = {yes},
journal = {Current Opinion in Nephrology and Hypertension},
note = {EVALuna2:3755},
pages = {14-20},
peerreviewed = {No},
title = {{A} different view on sodium balance},
volume = {24},
year = {2015}
}
@article{faucris.251062282,
abstract = {Aim: Recent evidence suggests that arterial hypertension could be alternatively explained as a physiological adaptation response to water shortage, termed aestivation, which relies on complex multi-organ metabolic adjustments to prevent dehydration. Here, we tested the hypothesis that chronic water loss across diseased skin leads to similar adaptive water conservation responses as observed in experimental renal failure or high salt diet. Methods: We studied mice with keratinocyte-specific overexpression of IL-17A which develop severe psoriasis-like skin disease. We measured transepidermal water loss and solute and water excretion in the urine. We quantified glomerular filtration rate (GFR) by intravital microscopy, and energy and nitrogen pathways by metabolomics. We measured skin blood flow and transepidermal water loss (TEWL) in conjunction with renal resistive indices and arterial blood pressure. Results: Psoriatic animals lost large amounts of water across their defective cutaneous epithelial barrier. Metabolic adaptive water conservation included mobilization of nitrogen and energy from muscle to increase organic osmolyte production, solute-driven maximal anti-diuresis at normal GFR, increased metanephrine and angiotensin 2 levels, and cutaneous vasoconstriction to limit TEWL. Heat exposure led to cutaneous vasodilation and blood pressure normalization without parallel changes in renal resistive index, albeit at the expense of further increased TEWL. Conclusion: Severe cutaneous water loss predisposes psoriatic mice to lethal dehydration. In response to this dehydration stress, the mice activate aestivation-like water conservation motifs to maintain their body hydration status. The circulatory water conservation response explains their arterial hypertension. The nitrogen-dependency of the metabolic water conservation response explains their catabolic muscle wasting.},
author = {Wild, Johannes and Jung, Rebecca and Knopp, Tanja and Efentakis, Panagiotis and Benaki, Dimitra and Grill, Alexandra and Wegner, Joanna and Molitor, Michael and Garlapati, Venkata and Rakova, Natalia and Markó, Lajos and Marton, Adriana and Mikros, Emmanuel and Münzel, Thomas and Kossmann, Sabine and Rauh, Manfred and Nakano, Daisuke and Kitada, Kento and Luft, Friedrich and Waisman, Ari and Wenzel, Philip and Titze, Jens and Karbach, Susanne},
doi = {10.1111/apha.13628},
faupublication = {yes},
journal = {Acta Physiologica},
keywords = {aestivation; catabolism; dehydration; double barrier concept; hypertension; transepidermal water loss},
note = {CRIS-Team Scopus Importer:2021-03-05},
peerreviewed = {Yes},
title = {{Aestivation} motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect},
year = {2021}
}
@article{faucris.108638904,
abstract = {Accurately collected 24-hour urine collections are presumed to be valid for estimating salt intake in individuals. We performed 2 independent ultralong-term salt balance studies lasting 105 (4 men) and 205 (6 men) days in 10 men simulating a flight to Mars. We controlled dietary intake of all constituents for months at salt intakes of 12, 9, and 6 g/d and collected all urine. The subjects' daily menus consisted of 27 279 individual servings, of which 83.0% were completely consumed, 16.5% completely rejected, and 0.5% incompletely consumed. Urinary recovery of dietary salt was 92% of recorded intake, indicating long-term steady-state sodium balance in both studies. Even at fixed salt intake, 24-hour urine collection for sodium excretion (UNaV) showed infradian rhythmicity. We defined a ±25 mmol deviation from the average difference between recorded sodium intake and UNaV as the prediction interval to accurately classify a 3-g difference in salt intake. Because of the biological variability in UNaV, only every other daily urine sample correctly classified a 3-g difference in salt intake (49%). By increasing the observations to 3 consecutive 24-hour collections and sodium intakes, classification accuracy improved to 75%. Collecting seven 24-hour urines and sodium intake samples improved classification accuracy to 92%. We conclude that single 24-hour urine collections at intakes ranging from 6 to 12 g salt per day were not suitable to detect a 3-g difference in individual salt intake. Repeated measurements of 24-hour UNaV improve precision. This knowledge could be relevant to patient care and the conduct of intervention trials.},
author = {Lerchl, Kathrin and Rakova, Natalia and Dahlmann, Anke and Rauh, Manfred and Goller, Ulrike and Basner, Mathias and Dinges, David F. and Beck, Luis and Agureev, Alexander and Larina, Irina and Baranov, Victor and Morukov, Boris and Eckardt, Kai-Uwe and Vassilieva, Galina and Wabel, Peter and Vienken, Joerg and Kirsch, Karl and Johannes, Bernd and Krannich, Alexander and Luft, Friedrich C. and Titze, Jens},
doi = {10.1161/HYPERTENSIONAHA.115.05851},
faupublication = {yes},
journal = {Hypertension},
note = {EVALuna2:3790},
pages = {850-7},
peerreviewed = {Yes},
title = {{Agreement} {Between} 24-{Hour} {Salt} {Ingestion} and {Sodium} {Excretion} in a {Controlled} {Environment}},
volume = {66},
year = {2015}
}
@article{faucris.118109684,
abstract = {Sodium balance is achieved within a matter of days and everything that enters should come out; sodium stores are of questionable relevance and sodium accumulation is accompanied by weight gain. Careful balance studies oftentimes conflicted with this view, and long-term studies suggested that total body sodium (TBNa) fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly related to cortisol. TBNa was not dependent on sodium intake, but instead exhibited far longer (greater than or equal to monthly) infradian rhythms independent of extracellular water, body weight or blood pressure. To discern the mechanisms further, we delved into sodium magnetic resonance imaging (Na-MRI) to identify sodium storage clinically. We found that sodium stores are greater in men than in women, increase with age and are higher in hypertensive than normotensive persons. We have suggestive evidence that these sodium stores can be mobilized, also in dialysis patients. The observations are in accordance with our findings that immune cells regulate a hypertonic interface in the skin interstitium that could serve as a protective barrier. Returning to our balance studies, we found that due to biological variability in 24-h sodium excretion, collecting urine for a day could not separate 12, 9 or 6 g/day sodium intakes with the precision of tossing a coin. Every other daily urine sampling correctly classified a 3-g difference in salt intake less than half the time, making the gold standard 24-h urine collection of little value in predicting salt intake. We suggest that wobbles in expected outcomes can lead to novel clinical insights even with respect to banal salt questions.},
author = {Titze, Jens and Rakova, Natalia and Kopp, Christoph and Dahlmann, Anke and Jantsch, Jonathan and Luft, Friedrich C.},
doi = {10.1093/ndt/gfv343},
faupublication = {yes},
journal = {Nephrology Dialysis Transplantation},
note = {EVALuna2:3836},
pages = {1078-81},
peerreviewed = {Yes},
title = {{Balancing} wobbles in the body sodium},
volume = {31},
year = {2016}
}
@article{faucris.284144926,
abstract = {We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.},
author = {Ogura, Takahiro and Kitada, Kento and Morisawa, Norihiko and Fujisawa, Yoshihide and Kidoguchi, Satoshi and Nakano, Daisuke and Kobara, Hideki and Masaki, Tsutomu and Titze, Jens and Nishiyama, Akira},
doi = {10.1038/s41440-022-01044-6},
faupublication = {yes},
journal = {Hypertension Research},
note = {CRIS-Team WoS Importer:2022-10-28},
peerreviewed = {Yes},
title = {{Contributions} of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats},
year = {2022}
}
@article{faucris.110181984,
abstract = {The skin can serve as an interstitial Na(+) reservoir. Local tissue Na(+) accumulation increases with age, inflammation and infection. This increased local Na(+) availability favors pro-inflammatory immune cell function and dampens their anti-inflammatory capacity. In this review, we summarize available data on how NaCl affects various immune cells. We particularly focus on how salt promotes pro-inflammatory macrophage and T cell function and simultaneously curtails their regulatory and anti-inflammatory potential. Overall, these findings demonstrate that local Na(+) availability is a promising novel regulator of immunity. Hence, the modulation of tissue Na(+) levels bears broad therapeutic potential: increasing local Na(+) availability may help in treating infections, while lowering tissue Na(+) levels may be used to treat, for example, autoimmune and cardiovascular diseases.},
author = {Schatz, Valentin and Neubert, Patrick and Schröder, Agnes and Binger, Katrina and Gebhard, Matthias and Mueller, Dominik N. and Luft, Friedrich C. and Titze, Jens and Jantsch, Jonathan},
doi = {10.1007/s00467-016-3349-x},
faupublication = {yes},
journal = {Pediatric Nephrology},
note = {EVALuna2:3894},
pages = {201-210},
peerreviewed = {Yes},
title = {{Elementary} immunology: {Na}(+) as a regulator of immunity},
volume = {32},
year = {2017}
}
@article{faucris.212418062,
abstract = {Long-term elevated blood sugar levels result in tissue matrix compositional changes in patients with diabetes mellitus type 2 (T2DM). We hypothesized that hemodialysis patients with T2DM might accumulate more tissue sodium than control hemodialysis patients. To test this, 23Na magnetic resonance imaging (23Na MRI) was used to estimate sodium in skin and muscle tissue in hemodialysis patients with or without T2DM. Muscle fat content was estimated by 1H MRI and tissue sodium content by 23Na MRI pre- and post-hemodialysis in ten hemodialysis patients with T2DM and in 30 matched control hemodialysis patients. We also assessed body fluid distribution with the Body Composition Monitor. 1H MRI indicated a tendency to higher muscle fat content in hemodialysis patients with T2DM compared to non-diabetic hemodialysis patients. 23Na MRI indicated increased sodium content in muscle and skin tissue of hemodialysis patients with T2DM compared to control hemodialysis patients. Multi-frequency bioimpedance was used to estimate extracellular water (ECW), and excess ECW in T2DM hemodialysis patients correlated with HbA1c levels. Sodium mobilization during hemodialysis lowered muscle sodium content post-dialysis to a greater degree in T2DM hemodialysis patients than in control hemodialysis patients. Thus, our findings provide evidence that increased sodium accumulation occurs in hemodialysis patients with T2DM and that impaired serum glucose metabolism is associated with disturbances in tissue sodium and water content.},
author = {Kopp, Christoph and Linz, Peter and Maier, Carolin and Wabel, Peter and Hammon, Matthias and Nagel, Armin Michael and Rosenhauer, Daniela and Horn, Stephan and Uder, Michael and Luft, Friedrich C. and Titze, Jens and Dahlmann, Anke},
doi = {10.1016/j.kint.2017.11.021},
faupublication = {yes},
journal = {Kidney International},
note = {EVALuna2:34700},
pages = {1191-1197},
peerreviewed = {Yes},
title = {{Elevated} tissue sodium deposition in patients with type 2 diabetes on hemodialysis detected by {23Na} magnetic resonance imaging},
volume = {93},
year = {2018}
}
@article{faucris.109000364,
abstract = {The current study was designed to determine whether vascular endothelial-derived endothelin-1 (ET-1) is important for skin Na(+) buffering. In control mice (C57BL/6J), plasma Na(+) and osmolarity were significantly elevated in animals on high- vs. low-salt (HS and LS, respectively) intake. The increased plasma Na(+) and osmolarity were associated with increased ET-1 mRNA in vascular tissue. There was no detectable difference in skin Na(+):H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na(+):H2O was significantly increased by blockade of the endothelin type A receptor with ABT-627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half-maximal inhibitory concentration, 0.055 nM). ET-1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9 pg/mg vs. 106.4 ± 6.8 pg/mg; P < 0.05), but not in vascular endothelial cell endothelin-1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na(+):H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET-1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET-1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na(+).},
author = {Speed, Joshua S. and Heimlich, J. Brett and Hyndman, Kelly A. and Fox, Brandon M. and Patel, Vivek and Yanagisawa, Masashi and Pollock, Jennifer S. and Titze, Jens and Pollock, David M.},
doi = {10.1096/fj.15-276584},
faupublication = {no},
journal = {The FASEB Journal},
note = {EVALuna2:3884},
pages = {4937-44},
peerreviewed = {Yes},
title = {{Endothelin}-1 as a master regulator of whole-body {Na}+ homeostasis},
volume = {29},
year = {2015}
}
@article{faucris.210620707,
author = {Titze, Jens},
doi = {10.3945/ajcn.117.158147},
faupublication = {yes},
journal = {American Journal of Clinical Nutrition},
note = {EVALuna2:35436},
pages = {1253-1254},
peerreviewed = {No},
title = {{Estimating} salt intake in humans: not so easy!},
volume = {105},
year = {2017}
}
@article{faucris.216848694,
abstract = {Infection and inflammation are able to induce diet-independent Na
+
-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na
+
-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na
+
(HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na
+
-modulated cell autonomous innate immunity. Abbreviations: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H
2
DCFDA: 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; E. coli: Escherichia coli; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H
+
-ATPase; WT: wild type.},
author = {Neubert, Patrick and Weichselbaum, Andrea and Reitinger, Carmen and Schatz, Valentin and Schröder, Agnes and Ferdinand, John R. and Simon, Michaela and Bär, Anna Lorena and Brochhausen, Christoph and Gerlach, Roman G. and Tomiuk, Stefan and Hammer, Karin and Wagner, Stefan and van Zandbergen, Ger and Binger, Katrina J. and Müller, Dominik N. and Kitada, Kento and Clatworthy, Menna R. and Kurts, Christian and Titze, Jens and Abdullah, Zeinab and Jantsch, Jonathan},
doi = {10.1080/15548627.2019.1596483},
faupublication = {no},
journal = {Autophagy},
keywords = {Autophagy; cell-autonomous immunity; E. coli; macrophage; salt; sodium},
note = {CRIS-Team Scopus Importer:2019-05-02},
peerreviewed = {Yes},
title = {{HIF1A} and {NFAT5} coordinate {Na}+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting},
year = {2019}
}
@article{faucris.210619029,
abstract = {The common notion is that the body Na+ is maintained within narrow limits for fluid and blood pressure homeostasis. Several studies have, however, shown that considerable amounts of Na+ can be retained or removed from the body without commensurate water loss and that the skin can serve as a major salt reservoir. Our own data from rats have suggested that the skin is hypertonic compared with plasma on salt storage and that this also applies to skin interstitial fluid. Even small electrolyte gradients between plasma and interstitial fluid would represent strong edema-generating forces. Because the water accumulation has been shown to be modest, we decided to reexamine with alternative methods in rats whether interstitial fluid is hypertonic during salt accumulation induced by high-salt diet (8% NaCl and 1% saline to drink) or deoxycorticosterone pellet implantation. These treatments resulted both in increased systemic blood pressure, skin salt, and water accumulation and in skin hyperosmolality. Interstitial fluid isolated from implanted wicks and lymph draining the skin was, however, isosmotic, and Na+ concentration in fluid isolated by centrifugation and in lymph was not different from plasma. Interestingly, by eluting layers of the skin, we could show that there was an osmolality and urea gradient from epidermis to dermis. Collectively, our data suggest that fluid leaving the skin as lymph is isosmotic to plasma but also that the skin can differentially control its own electrolyte microenvironment by creating local gradients that may be functionally important.
},
author = {Nikpey, Elham and Karlsen, Tine V. and Rakova, Natalia and Titze, Jens and Tenstad, Olav and Wiig, Helge},
doi = {10.1161/HYPERTENSIONAHA.116.08539},
faupublication = {yes},
journal = {Hypertension},
note = {EVALuna2:35439},
pages = {660-668},
peerreviewed = {Yes},
title = {{High}-{Salt} {Diet} {Causes} {Osmotic} {Gradients} and {Hyperosmolality} in {Skin} {Without} {Affecting} {Interstitial} {Fluid} and {Lymph}},
volume = {69},
year = {2017}
}
@article{faucris.121659824,
abstract = {A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.},
author = {Binger, Katrina J. and Gebhardt, Matthias and Heinig, Matthias and Rintisch, Carola and Schröder, Agnes and Neuhofer, Wolfgang and Hilgers, Karl Friedrich and Manzel, Arndt and Schwartz, Christian and Kleinewietfeld, Markus and Voelkl, Jakob and Schatz, Valentin and Linker, Ralf and Lang, Florian and Vöhringer, David and Wright, Mark D. and Hubner, Norbert and Dechend, Ralf and Jantsch, Jonathan and Titze, Jens and Mueller, Dominik N.},
doi = {10.1172/JCI80919},
faupublication = {yes},
journal = {Journal of Clinical Investigation},
note = {EVALuna2:3819},
pages = {4223-38},
peerreviewed = {Yes},
title = {{High} salt reduces the activation of {IL}-4- and {IL}-13-stimulated macrophages},
volume = {125},
year = {2015}
}
@article{faucris.226655683,
abstract = {The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.},
author = {Wiig, Helge and Schröder, Agnes and Neuhofer, Wolfgang and Jantsch, Jonathan and Kopp, Christoph and Karlsen, Tine V. and Boschmann, Michael and Goss, Jennifer and Bry, Maija and Rakova, Natalia and Dahlmann, Anke and Brenner, Sven and Tenstad, Olav and Nurmi, Harri and Mervaala, Eero and Wagner, Hubertus and Beck, Franz-Xaver and Mueller, Dominik N. and Kerjaschki, Dontscho and Luft, Friedrich C. and Harrison, David G. and Alitalo, Kari and Titze, Jens},
doi = {10.1172/JCI60113},
faupublication = {yes},
journal = {Journal of Clinical Investigation},
note = {EVALuna2:7617},
pages = {2803-15},
peerreviewed = {Yes},
title = {{Immune} cells control skin lymphatic electrolyte homeostasis and blood pressure},
volume = {123},
year = {2013}
}
@article{faucris.204726686,
abstract = {BACKGROUND: The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions.
METHODS: Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance.
RESULTS: A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion.
CONCLUSION: Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion.
FUNDING: Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.},
author = {Rakova, Natalia and Kitada, Kento and Lerchl, Kathrin and Dahlmann, Anke and Birukov, Anna and Daub, Steffen and Kopp, Christoph and Pedchenko, Tetyana and Zhang, Yahua and Beck, Luis and Johannes, Bernd and Marton, Adriana and Mueller, Dominik N. and Rauh, Manfred and Luft, Friedrich C. and Titze, Jens},
doi = {10.1172/JCI88530},
faupublication = {yes},
journal = {Journal of Clinical Investigation},
note = {EVALuna2:34240},
pages = {1932-1943},
peerreviewed = {Yes},
title = {{Increased} salt consumption induces body water conservation and decreases fluid intake},
volume = {127},
year = {2017}
}
@article{faucris.267622891,
abstract = {A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.},
author = {Sehnert, Bettina and Pohle, Sandy and Heuberger, Cornelia and Rzepka, Rita and Seidl, Maximilian and Nimmerjahn, Falk and Chevalier, Nina and Titze, Jens and Voll, Reinhard E.},
doi = {10.3389/fimmu.2021.765741},
faupublication = {yes},
journal = {Frontiers in Immunology},
keywords = {collagen-induced arthritis; cytokines; diet; serum transfer-induced arthritis; sodium chloride},
note = {CRIS-Team Scopus Importer:2021-12-31},
peerreviewed = {Yes},
title = {{Low}-{Salt} {Diet} {Attenuates} {B}-{Cell}- and {Myeloid}-{Cell}-{Driven} {Experimental} {Arthritides} by {Affecting} {Innate} as {Well} as {Adaptive} {Immune} {Mechanisms}},
volume = {12},
year = {2021}
}
@article{faucris.109436404,
abstract = {The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II-induced (Ang II-induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk-/- mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk-/- mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-?-producing CD8+ T cells in the spleen and kidneys of Lnk-/- mice compared with WT mice. Moreover, IFN-? deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.},
author = {Saleh, Mohamed A. and Mcmaster, William G. and Wu, Jing and Norlander, Allison E. and Funt, Samuel A. and Thabet, Salim R. and Kirabo, Annet and Xiao, Liang and Chen, Wei and Itani, Hana A. and Michell, Danielle and Huan, Tianxiao and Zhang, Yahua and Takaki, Satoshi and Titze, Jens and Levy, Daniel and Harrison, David G. and Madhur, Meena S.},
doi = {10.1172/JCI76327},
faupublication = {no},
journal = {Journal of Clinical Investigation},
note = {EVALuna2:3757},
pages = {1189-202},
peerreviewed = {Yes},
title = {{Lymphocyte} adaptor protein {LNK} deficiency exacerbates hypertension and end-organ inflammation},
volume = {125},
year = {2015}
}
@article{faucris.107933584,
abstract = {Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders.},
author = {Jantsch, Jonathan and Binger, Katrina J. and Mueller, Dominik N. and Titze, Jens},
doi = {10.3389/fphys.2014.00146},
faupublication = {yes},
journal = {Frontiers in Physiology},
note = {EVALuna2:3709},
pages = {146},
peerreviewed = {Yes},
title = {{Macrophages} in homeostatic immune function},
volume = {5},
year = {2014}
}
@article{faucris.123659844,
abstract = {We have previously reported that sodium is stored in skin and muscle. The amounts stored in hemodialysis (HD) patients are unknown. We determined whether (23)Na magnetic resonance imaging (sodium-MRI) allows assessment of tissue sodium and its removal in 24 HD patients and 27 age-matched healthy controls. We also studied 20 HD patients before and shortly after HD with a batch dialysis system with direct measurement of sodium in dialysate and ultrafiltrate. Age was associated with higher tissue sodium content in controls. This increase was paralleled by an age-dependent decrease of circulating levels of vascular endothelial growth factor-C (VEGF-C). Older (>60 years) HD patients showed increased sodium and water in skin and muscle and lower VEGF-C levels compared with age-matched controls. After HD, patients with low VEGF-C levels had significantly higher skin sodium content compared with patients with high VEGF-C levels (low VEGF-C: 2.3 ng/ml and skin sodium: 24.3 mmol/l; high VEGF-C: 4.1 ng/ml and skin sodium: 18.2 mmol/l). Thus, sodium-MRI quantitatively detects sodium stored in skin and muscle in humans and allows studying sodium storage reduction in ESRD patients. Age and VEGF-C-related local tissue-specific clearance mechanisms may determine the efficacy of tissue sodium removal with HD. Prospective trials on the relationship between tissue sodium content and hard end points could provide new insights into sodium homeostasis, and clarify whether increased sodium storage is a cardiovascular risk factor.},
author = {Dahlmann, Anke and Dörfelt, Kathrin and Eicher, Florian and Linz, Peter and Kopp, Christoph and Mössinger, Irina and Horn, Stephan and Bueschges-Seraphin, Beatrix and Wabel, Peter and Hammon, Matthias and Eckardt, Kai-Uwe and Kotanko, Peter and Levin, Nathan W. and Johannes, Bernd and Uder, Michael and Luft, Friedrich C. and Mueller, Dominik N. and Titze, Jens and Cavallaro, Alexander Josef},
doi = {10.1038/ki.2014.269},
faupublication = {yes},
journal = {Kidney International},
note = {EVALuna2:3717},
pages = {434-41},
peerreviewed = {Yes},
title = {{Magnetic} resonance-determined sodium removal from tissue stores in hemodialysis patients},
volume = {87},
year = {2015}
}
@article{faucris.243612628,
abstract = {Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.},
author = {Marton, Adriana and Kaneko, Tatsuroh and Kovalik, Jean Paul and Yasui, Atsutaka and Nishiyama, Akira and Kitada, Kento and Titze, Jens},
doi = {10.1038/s41581-020-00350-x},
faupublication = {yes},
journal = {Nature Reviews Nephrology},
note = {CRIS-Team Scopus Importer:2020-10-09},
peerreviewed = {Yes},
title = {{Organ} protection by {SGLT2} inhibitors: role of metabolic energy and water conservation},
year = {2020}
}
@article{faucris.123834744,
abstract = {Sodium tissue content by Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and, in parallel, of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes leads to decreased tissue sodium content due to its pharmacological action.In a prospective, double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to dapagliflozin 10 mg o.d. and placebo for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analyzed the sodium content in the skin and muscles of the lower leg by the Na-MRI at baseline, after the first and second treatment phase of 6 weeks.Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11, p = 0.010) and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024) 24-hour ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline (24.1 ± 6.6 vs.22.7 ± 6.4 mmol/L; p = 0.013). No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 mmol/L, p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline.SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in sodium tissue content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes known to be salt sensitive and prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition.},
author = {Schmieder, Roland and Ott, Christian and Linz, Peter and Jumar, Agnes and Friedrich, Stefanie and Titze, Jens and Hammon, Matthias and Uder, Michael and Kistner, Iris},
faupublication = {yes},
journal = {Journal of Hypertension},
note = {EVALuna2:14604},
pages = {e76},
peerreviewed = {Yes},
title = {{OS} 12-03 {SGLT}-2-{INHIBITION} {WITH} {DAPAGLIFLOZIN} {REDUCES} {TISSUE} {SODIUM} {CONTENT}},
volume = {34 Suppl 1},
year = {2016}
}
@article{faucris.232905038,
abstract = {We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.},
author = {Morisawa, Norihiko and Kitada, Kento and Fujisawa, Yoshihide and Nakano, Daisuke and Yamazaki, Daisuke and Kobuchi, Shuhei and Li, Lei and Zhang, Yifan and Morikawa, Takashi and Konishi, Yoshio and Yokoo, Takashi and Luft, Friedrich C. and Titze, Jens and Nishiyama, Akira},
doi = {10.1038/s41440-019-0389-1},
faupublication = {yes},
journal = {Hypertension Research},
keywords = {Heart rate; Renal sympathetic nervous system; Salt; Salt-sensitive hypertension},
note = {CRIS-Team Scopus Importer:2020-01-31},
peerreviewed = {Yes},
title = {{Renal} sympathetic nerve activity regulates cardiovascular energy expenditure in rats fed high salt},
year = {2020}
}
@article{faucris.210748692,
abstract = {In response to salt loading, Na+ and Cl- accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C-vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar-Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure-natriuresis curve. Without affecting body weight, plasma Na+ concentration or renal function, Na+ and Cl- skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.},
author = {Lankhorst, Stephanie and Severs, David and Marko, Lajos and Rakova, Natalia and Titze, Jens and Mueller, Dominik N. and Danser, A. H. Jan and Van Den Meiracker, Anton H.},
doi = {10.1161/HYPERTENSIONAHA.116.08565},
faupublication = {yes},
journal = {Hypertension},
note = {EVALuna2:35438},
pages = {919-926},
peerreviewed = {Yes},
title = {{Salt} {Sensitivity} of {Angiogenesis} {Inhibition}-{Induced} {Blood} {Pressure} {Rise}: {Role} of {Interstitial} {Sodium} {Accumulation}?},
volume = {69},
year = {2017}
}
@article{faucris.106718524,
abstract = {Sodium tissue content by 23Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes characterized by sodium retention leads to decreased tissue sodium content due to its pharmacological action.In a prospective double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to either dapagliflozin 10 mg or placebo once daily for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analysed the sodium content in the skin and muscles of the lower leg by Na-MRI.Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11 mmHg, p = 0.010), and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024), 24-h ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline [24.1 ± 6.6 vs. 22.7 ± 6.4 A.U.(arbitrary unit) p = 0.013]. No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 A.U. p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline.SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in tissue sodium content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT02383238) retrospectively registered.},
author = {Karg, Margarete and Bosch, A. and Kannenkeril, D. and Striepe, Kristina and Ott, Christian and Schneider, M. P. and Boemke-Zelch, Franziska and Linz, Peter and Nagel, Armin Michael and Titze, Jens and Uder, Michael and Schmieder, Roland},
doi = {10.1186/s12933-017-0654-z},
faupublication = {yes},
journal = {Cardiovascular Diabetology},
note = {EVALuna2:4043},
pages = {5},
peerreviewed = {Yes},
title = {{SGLT}-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial},
volume = {17},
year = {2018}
}
@article{faucris.123862024,
abstract = {The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using (23)sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (r=0.33, P=0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (r=0.56, P<0.001 versus r=0.35, P<0.001; P<0.01 between the two correlations). Linear regression analysis demonstrated that skin sodium content is a strong explanatory variable for left ventricular mass, unaffected by BP and total body overhydration. In conclusion, we found skin sodium content to be closely linked to left ventricular mass in patients with CKD. Interventions that reduce skin sodium content might improve cardiovascular outcomes in these patients.},
author = {Schneider, Markus P. and Raff, Ulrike and Kopp, Christoph and Scheppach, Johannes B. and Toncar, Sebastian and Wanner, Christoph and Schlieper, Georg and Saritas, Turgay and Floege, Juergen and Schmid, Matthias and Birukov, Anna and Dahlmann, Anke and Linz, Peter and Janka, Rolf Matthias and Uder, Michael and Schmieder, Roland and Titze, Jens and Eckardt, Kai-Uwe},
doi = {10.1681/ASN.2016060662},
faupublication = {yes},
journal = {Journal of the American Society of Nephrology},
note = {EVALuna2:3863},
peerreviewed = {Yes},
title = {{Skin} {Sodium} {Concentration} {Correlates} with {Left} {Ventricular} {Hypertrophy} in {CKD}},
year = {2017}
}
@article{faucris.120950544,
abstract = {Skin sodium (Na(+) ) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na(+) storage in humans ((23) Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution (23) Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean ± standard deviation, 46 ± 18 years; range, 20-79 years) were investigated. Transverse slices of the calf were imaged with (23) Na MRI using a high in-plane resolution of 0.9 × 0.9 mm(2) . Skin Na(+) content was determined using external agarose standards covering a physiological range of Na(+) concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na(+) content was investigated. The (23) Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na(+) content in the volunteer population was <10.3%. An age-dependent increase in skin Na(+) content was observed (r = 0.78). The assignment of Na(+) stores with (23) Na MRI techniques could be improved at 7.0 T compared with current 3.0 T technology. The benefits of such improvements may have the potential to aid basic research and clinical applications designed to unlock questions regarding the Na(+) balance and Na(+) storage function of skin.},
author = {Linz, Peter and Santoro, Davide and Renz, Wolfgang and Rieger, Jan and Ruehle, Anjuli and Ruff, Jan and Deimling, Michael and Rakova, Natalia and Muller, Dominik N. and Luft, Friedrich C. and Titze, Jens and Niendorf, Thoralf},
doi = {10.1002/nbm.3224},
faupublication = {yes},
journal = {NMR in Biomedicine},
note = {EVALuna2:3754},
pages = {54-62},
peerreviewed = {Yes},
title = {{Skin} sodium measured with {²³Na} {MRI} at 7.0 {T}},
volume = {28},
year = {2015}
}
@article{faucris.234654778,
abstract = {Space medicine and new technology such as magnetic resonance imaging of tissue sodium stores ((NaMRI)-Na-23) have changed our understanding of human sodium homeostasis and pathophysiology. It has become evident that body sodium comprises 3 main components. Two compartments have been traditionally recognized, namely one that is circulating and systemically active via its osmotic action, and one slowly exchangeable pool located in the bones. The third, recently described pool represents sodium stored in skin and muscle interstitium, and it is implicated in cell and biologic activities via local hypertonicity and sodium clearance mechanisms. This in-depth review provides a comprehensive view on the pathophysiology and existing knowledge gaps of systemic hemodynamic and tissue sodium accumulation in dialysis patients. Furthermore, we discuss how the combination of novel technologies to quantitate tissue salt accumulation (e.g., (NaMRI)-Na-23) with devices to facilitate the precise attainment of a prescribed hemodialytic sodium mass balance (e.g., sodium and water balancing modules) will improve our therapeutic approach to sodium management in dialysis patients. While prospective studies are required, we think that these new diagnostic and sodium balancing tools will enhance our ability to pursue more personalized therapeutic interventions on sodium and water management, with the eventual goal of improving dialysis patient outcomes.},
author = {Canaud, Bernard and Kooman, Jeroen and Selby, Nicholas M. and Taal, Maarten and Francis, Susan and Kopperschmidt, Pascal and Maierhofer, Andreas and Kotanko, Peter and Titze, Jens},
doi = {10.1016/j.kint.2018.09.024},
faupublication = {yes},
journal = {Kidney International},
note = {CRIS-Team WoS Importer:2020-02-21},
pages = {296-309},
peerreviewed = {Yes},
title = {{Sodium} and water handling during hemodialysis: new pathophysiologic insights and management approaches for improving outcomes in end-stage kidney disease},
volume = {95},
year = {2019}
}
@article{faucris.106880884,
abstract = {The equilibration theory of extracellular body fluids is tightly linked to sodium (Na) metabolism. It is accepted that with changes in salt intake, renal sodium elimination will prevent any change in interstitial Na content and concentration. This review summarizes recent anomalous findings regarding salt and water homeostasis that are inconsistent with current assumptions.Recent findings from chemical analysis studies of laboratory animals, as well as noninvasive quantitative Na MRI (Na-MRI) studies in patients, have shown that remarkable amounts of Na are stored in muscle and in skin without commensurate water retention. Furthermore, an ultra-long Na balance study in humans suggests the presence of endogenous clocks that generate weekly and monthly infradian rhythmicity of Na storage independent of salt intake. Animal experiments suggest that fluids in the skin interstitium are hypertonic compared with plasma, and that interstitial osmotic stress induces local extrarenal immune cell and lymph-capillary driven mechanisms for electrolyte clearance and maintenance of the internal environment.Recent quantitative evidence challenges current ideas on salt and water homeostasis, and suggests that Na homeostasis cannot be maintained without additional previously unappreciated extrarenal regulatory mechanisms.},
author = {Titze, Jens},
doi = {10.1097/01.mnh.0000441151.55320.c3},
faupublication = {yes},
journal = {Current Opinion in Nephrology and Hypertension},
note = {EVALuna2:3657},
pages = {101-5},
peerreviewed = {Yes},
title = {{Sodium} balance is not just a renal affair},
volume = {23},
year = {2014}
}
@article{faucris.241507323,
abstract = {Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure, renal disease, stroke, and cancer. Therefore, considerable research has been expended on the mechanism of sodium handling based on the current concepts of sodium balance. The studies have necessarily relied on relatively short-term experiments and focused on extremes of salt intake in humans. Ultra-long-term salt balance has received far less attention. We performed long-term salt balance studies at intakes of 6, 9, and 12 g/day and found that although the kidney remains the long-term excretory gate, tissue and plasma sodium concentrations are not necessarily the same and that urinary salt excretion does not necessarily reflect total-body salt content. We found that to excrete salt, the body makes a great effort to conserve water, resulting in a natriuretic-ureotelic principle of salt excretion. Of note, renal sodium handling is characterized by osmolyte excretion with anti-parallel water reabsorption, a state-of-affairs that is achieved through the interaction of multiple organs. In this review, we discuss novel sodium and water balance concepts in reference to our ultra-long-term study. An important key to understanding body sodium metabolism is to focus on water conservation, a biological principle to protect from dehydration, since excess dietary salt excretion into the urine predisposes to renal water loss because of natriuresis. We believe that our research direction is relevant not only to salt balance but also to cardiovascular regulatory mechanisms.},
author = {Minegishi, Shintaro and Luft, Friedrich C. and Titze, Jens and Kitada, Kento},
doi = {10.1093/ajh/hpaa049},
faupublication = {yes},
journal = {American Journal of Hypertension},
keywords = {blood pressure; body fluid; energy metabolism; estivation; hypertension; osmolyte; salt; urea},
note = {CRIS-Team Scopus Importer:2020-08-14},
pages = {687-694},
peerreviewed = {Yes},
title = {{Sodium} {Handling} and {Interaction} in {Numerous} {Organs}},
volume = {33},
year = {2020}
}
@article{faucris.123929564,
abstract = {Current teaching states that when sodium intake is increased from low to high levels, total-body sodium (TBNa) and water increase until daily sodium excretion again equals intake. When sodium intake is reduced, sodium excretion briefly exceeds intake until the excess TBNa and water are eliminated, at which point sodium excretion again equals intake. However, careful balance studies oftentimes conflict with this view and long-term studies suggest that TBNa fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for several weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly to cortisol. TBNa was not dependent on sodium intake but instead exhibited far longer (>= monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. The findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing (23)Na-magnetic resonance imaging (MRI) to pursue open questions on sodium balance in patients. Our findings could be relevant to therapeutic strategies for hypertension and target-organ damage.},
author = {Titze, Jens and Dahlmann, Anke and Lerchl, Kathrin and Kopp, Christoph and Rakova, Natalia and Schröder, Agnes and Luft, Friedrich C.},
doi = {10.1038/ki.2013.367},
faupublication = {yes},
journal = {Kidney International},
note = {EVALuna2:3656},
pages = {759-67},
peerreviewed = {Yes},
title = {{Spooky} sodium balance},
volume = {85},
year = {2014}
}
@article{faucris.309912775,
abstract = {Introduction: Typical Western diet, rich in salt, contributes to autoimmune disease development. However, conflicting reports exist about the effect of salt on neutrophil effector functions, also in the context of arthritis. Methods: We investigated the effect of sodium chloride (NaCl) on neutrophil viability and functions in vitro, and in vivo employing the murine K/BxN-serum transfer arthritis (STA) model. Results and discussion: The effects of NaCl and external reactive oxygen species (H2O2) were further examined on osteoclasts in vitro. Hypertonic sodium-rich media caused primary/secondary cell necrosis, altered the nuclear morphology, inhibited phagocytosis, degranulation, myeloperoxidase (MPO) peroxidation activity and neutrophil extracellular trap (NET) formation, while increasing total ROS production, mitochondrial ROS production, and neutrophil elastase (NE) activity. High salt diet (HSD) aggravated arthritis by increasing inflammation, bone erosion, and osteoclast differentiation, accompanied by increased NE expression and activity. Osteoclast differentiation was decreased with 25 mM NaCl or 100 nM H2O2 addition to isotonic media. In contrast to NaCl, external H2O2 had pro-resorptive effects in vitro. We postulate that in arthritis under HSD, increased bone erosion can be attributed to an enhanced oxidative milieu maintained by infiltrating neutrophils, rather than a direct effect of NaCl.},
author = {Zlatar, Leticija and Mahajan, Aparna and Munoz Becerra, Marco and Weidner, Daniela and Bila, Galyna and Bilyy, Rostyslav and Titze, Jens and Hoffmann, Markus H. and Schett, Georg and Herrmann, Martin and Steffen, Ulrike and Muñoz, Luis E. and Knopf, Jasmin},
doi = {10.3389/fimmu.2023.1174537},
faupublication = {yes},
journal = {Frontiers in Immunology},
keywords = {K/BxN serum transfer arthritis; neutrophil extracellular traps (NETs); neutrophils; osteoclasts; reactive oxygen species; sodium chloride},
note = {CRIS-Team Scopus Importer:2023-09-01},
peerreviewed = {Yes},
title = {{Suppression} of neutrophils by sodium exacerbates oxidative stress and arthritis},
volume = {14},
year = {2023}
}
@article{faucris.272205842,
abstract = {Hyperosmolality is common in critically ill patients during body fluid volume reduction. It is unknown whether this is only a result of decreased total body water or an active osmole-producing mechanism similar to that found in aestivating animals, where muscle degradation increases urea levels to preserve water. We hypothesized that fluid volume reduction in critically ill patients contributes to a shift from ionic to organic osmolytes similar to mechanisms of aestivation. We performed a post-hoc analysis on data from a multicenter observational study in adult intensive care unit (ICU) patients in the postresuscitative phase. Fluid, electrolyte, energy and nitrogen intake, fluid loss, estimated glomerular filtration rate (eGFR), and estimated plasma osmolality (eOSM) were registered. Contributions of osmolytes Na+, K+, urea, and glucose to eOSM expressed as proportions of eOSM were calculated. A total of 241 patients were included. eOSM increased (median change 7.4 mOsm/kg [IQR-1.9-18]) during the study. Sodium's and potassium's proportions of eOSM decreased (P P < .01, respectively), whereas urea's proportion increased (P < .001). The urea's proportion of eOSM was higher in patients with negative vs. positive fluid balance. Urea's proportion of eOSM increased with eOSM (r = 0.63; adjusted for eGFR r = 0.80), but not nitrogen intake. In patients without furosemide and/or renal replacement therapy (n = 17), urea's proportion of eOSM and eOSM correlated strongly (r = 0.92). Urea's proportion of eOSM was higher in patients not surviving up to 90 d. In stabilized ICU patients, the contribution of urea to plasma osmolality increased during body water volume reduction, statistically independently of nitrogen administration and eGFR. The shift from ionic osmolytes to urea during body fluid volume reduction is similar to that seen in aestivating animals.},
author = {Nihlen, Sandra and Frithiof, Robert and Titze, Jens and Kawati, Rafael and Rasmusson, Johan and Rylander, Christian and Pikwer, Andreas and Castegren, Markus and Belin, Anton and Hultstrom, Michael and Lipcsey, Miklos},
doi = {10.1093/function/zqab055},
faupublication = {yes},
journal = {Function},
note = {CRIS-Team WoS Importer:2022-04-01},
peerreviewed = {Yes},
title = {{The} {Contribution} of {Plasma} {Urea} to {Total} {Osmolality} {During} {Iatrogenic} {Fluid} {Reduction} in {Critically} {Ill} {Patients}},
volume = {3},
year = {2021}
}
@article{faucris.216710989,
abstract = {B lymphocytes, as a central part of adaptive immune responses, have the ability to fight against an almost unlimited numbers of pathogens. Impairment of B cell development, activation and differentiation to antibody secreting plasma cells can lead to malignancy, allergy, autoimmunity and immunodeficiency. However, the impact of environmental factors, such as hyperosmolality or osmotic stress caused by varying salt concentrations in different lymphoid organs, on these processes is not well-understood. Here, we report that B cells respond to osmotic stress in a biphasic manner. Initially, increased osmolality boosted B cell activation and differentiation as shown by an untimely downregulation of Pax5 as well as upregulation of CD138. However, in the second phase, we observed an increase in cell death and impaired plasmablast differentiation. Osmotic stress resulted in impaired class switch to IgG1, inhibition of phosphorylation of p38 mitogen-activated kinase and a delayed NFAT5 response. Overall, these findings demonstrate the importance of microenvironmental hyperosmolality and osmotic stress caused by NaCl for B cell activation and differentiation.},
author = {Cvetkovic, Ljiljana and Perisic, Stojan and Titze, Jens and Jäck, Hans-Martin and Schuh, Wolfgang},
doi = {10.3389/fimmu.2019.00828},
faupublication = {yes},
journal = {Frontiers in Immunology},
note = {CRIS-Team WoS Importer:2019-04-30},
peerreviewed = {Yes},
title = {{The} {Impact} of {Hyperosmolality} on {Activation} and {Differentiation} of {B} {Lymphoid} {Cells}},
volume = {10},
year = {2019}
}
@inproceedings{faucris.209090139,
author = {Rokvic, Ljiljana and Titze, Jens and Schuh, Wolfgang and Jäck, Hans-Martin},
faupublication = {yes},
note = {EVALuna2:13659},
pages = {-},
peerreviewed = {Yes},
title = {{The} importance of the {NFAT5}/{TonEBP}-{Inediated} osmotic stress response in {B} cells},
volume = {198 S},
year = {2017}
}
@article{faucris.275302440,
abstract = {We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2 receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.},
author = {Kidoguchi, Satoshi and Kitada, Kento and Fujisawa, Yoshihide and Nakano, Daisuke and Yokoo, Takashi and Titze, Jens and Nishiyama, Akira},
doi = {10.1016/j.jphs.2022.04.008},
faupublication = {yes},
journal = {Journal of Pharmacological Sciences},
keywords = {Blood pressure; Body fluid; Cardiovascular energy expenditure; Tolvaptan; Urea},
note = {CRIS-Team Scopus Importer:2022-05-20},
pages = {115-123},
peerreviewed = {Yes},
title = {{Tolvaptan} induces body fluid loss and subsequent water conservation in normal rats},
volume = {149},
year = {2022}
}
@article{faucris.204881352,
abstract = {BACKGROUND: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride.
OBJECTIVE: We were able to test the value of 24-h urine collections in a unique, ultra-long-term balance study conducted during a simulated trip to Mars.
DESIGN: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intake was maintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily.
RESULTS: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland-Altman analyses on the value of urine collections to estimate intake.
CONCLUSIONS: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals.},
author = {Birukov, Anna and Rakova, Natalia and Lerchl, Kathrin and Engberink, Rik H. G. Olde and Johannes, Bernd and Wabel, Peter and Moissl, Ulrich and Rauh, Manfred and Luft, Friedrich C. and Titze, Jens},
doi = {10.3945/ajcn.116.132951},
faupublication = {yes},
journal = {American Journal of Clinical Nutrition},
note = {EVALuna2:33935},
pages = {49-57},
peerreviewed = {Yes},
title = {{Ultra}-long-term human salt balance studies reveal interrelations between sodium, potassium, and chloride intake and excretion},
volume = {104},
year = {2016}
}