Schley, Gunnar and Klanke, Bernd and Kalucka, Joanna and Schatz, Valentin and Daniel, Christoph and Mayer, Marleen and Goppelt-Struebe, Margarete and Herrmann, Martin and Thorsteinsdottir, Margret and Palsson, Runolfur and Beneke, Angelika and Katschinski, Doerthe M. and Burzlaff, Nicolai and Eckardt, Kai-Uwe and Weidemann, Alexander and Jantsch, Jonathan and Willam, Carsten (2019) Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis. KIDNEY INTERNATIONAL, 96 (2). pp. 378-396. ISSN 0085-2538, 1523-1755
Full text not available from this repository. (Request a copy)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 F4/80D 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-1 alpha and myeloid cell-specific HIF-1 alpha and HIF-2 alpha 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPOXIA-INDUCIBLE FACTOR; CHRONIC KIDNEY-DISEASE; TUBULAR EPITHELIAL-CELLS; URETERAL OBSTRUCTION; DENDRITIC CELLS; HIF; MACROPHAGES; EXPRESSION; STABILIZATION; ACTIVATION; adenine; chronic inflammation; chronic kidney disease; hypoxia-inducible factor; mononuclear phagocyte; PHD inhibitor |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 06:58 |
| Last Modified: | 02 Apr 2020 06:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26567 |
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