RRC ID 62320
Author Uchida L, Tanaka T, Saito H, Sugahara M, Wakashima T, Fukui K, Nangaku M.
Title Effects of a prolyl hydroxylase inhibitor on kidney and cardiovascular complications in a rat model of chronic kidney disease.
Journal Am J Physiol Renal Physiol
Abstract 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 Nω-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.
Volume 318(2)
Pages F388-F401
Published 2020-2-1
DOI 10.1152/ajprenal.00419.2019
PMID 31841388
MeSH 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
IF 3.191
Human and Animal Cells P19.CL6(RCB2318)