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

Gunnar Schley, B. Klanke, Joanna Kalucka, Valentin Schatz, Christoph Daniel, Marleen Mayer, Margarete Goppelt-Struebe, Martin Herrmann, Margret Thorsteinsdottir, Runolfur Palsson, Angelika Beneke, Dörthe M. Katschinski, Nicolai Burzlaff, Kai Uwe Eckardt, Alexander Weidemann, Jonathan Jantsch, Carsten Willam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)378-396
Number of pages19
JournalKidney International
Volume96
Issue number2
DOIs
Publication statusPublished - Aug 2019

Bibliographical note

Funding
This study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; WI 1945/3-1 to CW, WE 4275/3-1 to AW, 387509280 SFB 1350 to JJ and CW, and SFB1181-C3 and KFO257 to MH) and the Graduate School of Molecular Science (GSMS) at Friedrich-Alexander-University Erlangen-Nürnberg (FAU; to MM).

Publisher Copyright:
© 2019 International Society of Nephrology

Other keywords

  • adenine
  • chronic inflammation
  • chronic kidney disease
  • hypoxia-inducible factor
  • mononuclear phagocyte
  • PHD inhibitor

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