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.