Hypoxia inducible factor stabilization improves defective ischemia-induced angiogenesis in a rodent model of chronic kidney disease

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Details zur Publikation

Autor(en): Schellinger IN, Cordasic N, Panesar J, Buchholz B, Jacobi J, Hartner A, Klanke B, Jakubiczka-Smorag J, Burzlaff N, Heinze E, Warnecke C, Raaz U, Willam C, Tsao PS, Eckardt KU, Amann KU, Hilgers KF
Zeitschrift: Kidney International
Jahr der Veröffentlichung: 2017
Band: 91
Heftnummer: 3
Seitenbereich: 616-627
ISSN: 0085-2538


Abstract


Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo: carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes (Vegf, Vegf-r1, Vegf-r2, Ho-1) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.



FAU-Autoren / FAU-Herausgeber

Amann, Kerstin Ute Prof. Dr.
Nephropathologische Abteilung im Pathologischen Institut
Burzlaff, Nicolai Prof. Dr.
Professur für Anorganische Chemie
Eckardt, Kai-Uwe Prof. Dr. med.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Waidmann, Eva
Professur für Anorganische Chemie
Hilgers, Karl Friedrich Prof. Dr. med.
Professur für Innere Medizin (Hochdruckforschung)
Schellinger, Isabel Nahal
Professur für Innere Medizin (Hochdruckforschung)
Warnecke, Christina PD Dr.
Medizinische Fakultät
Willam, Carsten Prof. Dr.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie


Autor(en) der externen Einrichtung(en)
Georg-August-Universität Göttingen
Stanford University


Zitierweisen

APA:
Schellinger, I.N., Cordasic, N., Panesar, J., Buchholz, B., Jacobi, J., Hartner, A.,... Hilgers, K.F. (2017). Hypoxia inducible factor stabilization improves defective ischemia-induced angiogenesis in a rodent model of chronic kidney disease. Kidney International, 91(3), 616-627. https://dx.doi.org/10.1016/j.kint.2016.09.028

MLA:
Schellinger, Isabel Nahal, et al. "Hypoxia inducible factor stabilization improves defective ischemia-induced angiogenesis in a rodent model of chronic kidney disease." Kidney International 91.3 (2017): 616-627.

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Zuletzt aktualisiert 2018-10-10 um 08:27