Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis

Journal article


Publication Details

Author(s): Schley G, Klanke B, Kalucka J, Schatz V, Daniel C, Mayer M, Goppelt-Strübe M, Herrmann M, Thorsteinsdottir M, Palsson R, Beneke A, Katschinski DM, Burzlaff N, Eckardt KU, Weidemann A, Jantsch J, Willam C
Journal: Kidney International
Publication year: 2019
ISSN: 0085-2538


Abstract

Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.


FAU Authors / FAU Editors

Burzlaff, Nicolai Prof. Dr.
Professur für Anorganische Chemie
Daniel, Christoph Prof. Dr.
Nephropathologische Abteilung im Pathologischen Institut
Eckardt, Kai-Uwe Prof. Dr. med.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Goppelt-Strübe, Margarete apl. Prof. Dr.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Herrmann, Martin Prof. Dr.
Medizinische Klinik 3 - Rheumatologie und Immunologie
Mayer, Marleen
Professur für Anorganische Chemie
Weidemann, Alexander PD Dr.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Willam, Carsten Prof. Dr.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie


External institutions with authors

Háskóli Íslands
Universitätsklinikum Göttingen
Universitätsklinikum Regensburg


How to cite

APA:
Schley, G., Klanke, B., Kalucka, J., Schatz, V., Daniel, C., Mayer, M.,... Willam, C. (2019). Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis. Kidney International. https://dx.doi.org/10.1016/j.kint.2019.02.016

MLA:
Schley, Gunnar, et al. "Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis." Kidney International (2019).

BibTeX: 

Last updated on 2019-17-06 at 15:53