Dokumentenart: | Artikel | ||||
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Titel eines Journals oder einer Zeitschrift: | Kidney International | ||||
Verlag: | Elsevier | ||||
Ort der Veröffentlichung: | NEW YORK | ||||
Band: | 96 | ||||
Nummer des Zeitschriftenheftes oder des Kapitels: | 2 | ||||
Seitenbereich: | S. 378-396 | ||||
Datum: | 2019 | ||||
Institutionen: | Medizin > Lehrstuhl für Medizinische Mikrobiologie und Hygiene | ||||
Identifikationsnummer: |
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Stichwörter / 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 | ||||
Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
Status: | Veröffentlicht | ||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||
An der Universität Regensburg entstanden: | Ja | ||||
Dokumenten-ID: | 48424 |
Zusammenfassung
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 ...
Zusammenfassung
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.
Metadaten zuletzt geändert: 03 Sep 2021 09:55