Effects of a prolyl hydroxylase inhibitor on kidney and cardiovascular complications in a rat model of chronic kidney disease

• Published in: American journal of physiology. Renal physiology Vol. 318; no. 2; pp. F388 - F401
• Main Authors: Uchida, Lisa, Tanaka, Tetsuhiro, Saito, Hisako, Sugahara, Mai, Wakashima, Takeshi, Fukui, Kenji, Nangaku, Masaomi
• Format: Journal Article
• Language: English
• Published: United States 01.02.2020
• Subjects: Animals; Apoptosis - drug effects; Cell Line; Cytokines - metabolism; Disease Models, Animal; Fibrosis; Hypertrophy, Left Ventricular - enzymology; Hypertrophy, Left Ventricular - etiology; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - prevention & control; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation Mediators - metabolism; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Male; Mitochondria, Heart - drug effects; Mitochondria, Heart - enzymology; Mitochondria, Heart - ultrastructure; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - ultrastructure; N-substituted Glycines - pharmacology; Neovascularization, Physiologic - drug effects; Prolyl Hydroxylases - metabolism; Prolyl-Hydroxylase Inhibitors - pharmacology; Pyridines - pharmacology; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - enzymology; Renal Insufficiency, Chronic - pathology; Signal Transduction; Triazoles - pharmacology; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects; cardiovascular disease; chronic kidney disease; prolyl hydroxylase inhibitor; hypoxia-inducible factor; cardiorenal syndrome
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00419.2019

Cardiovascular disease (CVD) is the main cause of death in patients with kidney disease. Hypoxia plays a crucial role in the progression of chronic kidney disease (CKD) and cardiovascular disease, which is associated with fibrosis, inflammation, and oxidative injury. Previous studies have indicated that prolyl hydroxylase (PHD) inhibitors, stabilizers of hypoxia-inducible factors (HIFs), can be used to treat acute organ injuries such as renal ischemia-reperfusion, myocardial infarction, and, in some contexts, CKD. However, the effects of PHD inhibitors on cardiovascular complications in CKD remain unknown. In the present study, we investigated whether HIF activation has a beneficial effect on kidney and cardiovascular outcomes in the remnant kidney model. We used the 5/6 nephrectomy model with the nitric oxide synthase inhibitor -nitro-l-arginine (20 mg/L in the drinking water). Rats received diet with 0.005% enarodustat (PHD inhibitor) or vehicle for 8 wk starting 2 wk before 5/6 nephrectomy. Activation of HIF by the PHD inhibitor reduced cardiac hypertrophy and ameliorated myocardial fibrosis in association with restored capillary density and improvement in mitochondrial morphology. With regard to kidneys, enarodustat ameliorated fibrosis in association with reduced proinflammatory cytokine expression, reduced apoptosis, and restored capillary density, even though renal endpoints such as proteinuria and serum creatinine levels were not significantly affected by enarodustat, except for blood urea nitrogen levels at 4 wk. In addition, cardiac hypertrophy marker genes, including atrial natriuretic peptide, were suppressed in P19CL6 cells treated with enarodustat. These findings suggest that PHD inhibitors might show beneficial effects in cardiovascular complications caused by CKD.