Abstract

Prolyl hydroxylase (PHD) inhibitors are being developed as alternatives to recombinant human erythropoietin (rHuEPO) for the treatment of anemia in patients with chronic kidney disease (CKD). However, the effects of PHD inhibitors and rHuEPO on blood pressure and CKD in animal models susceptible to hypertension and nephropathy have not been studied. The present study compared the effects of dimethyloxaloylglycine (DMOG), a PHD inhibitor, and rHuEPO on the development of hypertension and renal injury in Dahl salt-sensitive rats fed an 8% salt diet for 3 weeks. DMOG and rHuEPO were equally effective at raising hemoglobin levels. Systolic blood pressure rose to a greater extent in rHuEPO-treated rats (267 ± 10 versus 226 ± 4 mmHg) than in rats given DMOG (189 ± 8 mmHg). Urinary protein excretion increased to 568 ± 54 versus 353 ± 25 mg/day in rats treated with rHuEPO and vehicle; however it only rose to 207 ± 21 mg/day in rats receiving DMOG. DMOG significantly attenuated the degree of glomerulosclerosis and renal interstitial fibrosis as compared to that in vehicle and rHuEPO-treated rats. This was associated with lower renal levels of MCP-1, IL-1β, and increased VEGF expression in cortex and medulla. These results indicate that DMOG and rHuEPO are equally effective in increasing hemoglobin levels in Dahl S rats; however rHuEPO aggravates hypertension and renal injury, whereas DMOG has marked renoprotective effects. These results suggest that PHD inhibitors may have a therapeutic advantage for the treatment of anemia in CKD.