• Sota Kato, Teisuke Takahashi, Noriyuki Miyata, and Richard J Roman.
• Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (S.K., R.J.R.); and Pharmacology Laboratories (S.K., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
• J. Pharmacol. Exp. Ther. 2020 Feb 1; 372 (2): 166-174.

AbstractProlyl 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 vs. 226 ± 4 mm Hg) than in rats given DMOG (189 ± 8 mm Hg). 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 with that in vehicle and rHuEPO-treated rats. This was associated with lower renal levels of monocyte chemoattractant protein-1 and interleukin-1β and increased vascular endothelial growth factor 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. SIGNIFICANCE STATEMENT: Prolyl hydroxylase (PHD) inhibitors are in phase 3 clinical trials as alternatives to recombinant human erythropoietin (rHuEPO) for the treatment of anemia in chronic kidney disease (CKD). The present study reveals that dimethyloxaloylglycine (DMOG), a PHD inhibitor, and rHuEPO are equally effective in increasing hemoglobin levels in Dahl S rats; however, rHuEPO aggravated hypertension and renal injury, whereas DMOG attenuated the development of hypertension and prevented renal injury. PHD inhibitors may provide a safer therapeutic option for the treatment of anemia in CKD.Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

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