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

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 (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Kidney International Nature Publishing Group: Open Access Hybrid Model Option A

DOI: 10.1016/j.kint.2019.02.016

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.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology Marleen Mayer Professur für Anorganische Chemie Margarete Goppelt-Strübe Department of Medicine 4 – Nephrology and Hypertension Martin Herrmann Department of Medicine 3 – Rheumatology and Immunology Nicolai Burzlaff Professur für Anorganische Chemie Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension Alexander Weidemann Department of Medicine 4 – Nephrology and Hypertension Carsten Willam Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Universitätsklinikum Göttingen DE Germany (DE) University of Iceland (UI) / Háskóli Íslands IS Iceland (IS)

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).

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