Pharmacological HIF?PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation

Aim Hypoxia-inducible factors (HIFs) are O2-sensitive transcription that regulate multiple biological processes which essential for cellular adaptation to hypoxia. Small molecule inhibitors of HIF-prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-dependent transcriptional programs and have broad clinical potential. HIF-PHIs currently in global late-stage development the treatment anaemia associated with chronic kidney disease. Although effects hypoxia on renal haemodynamics function been studied animal models humans living at high altitude, pharmacological HIF activation haemodynamics, O2 metabolism metabolic efficiency not well understood. Methods Using a cross-sectional study design, we investigated metabolism, gene expression NO production healthy rats treated different doses roxadustat or molidustat compared vehicle control. Results Systemic administration resulted dose-dependent reduction renovascular resistance (RVR). This was increased glomerular filtration rate (GFR), urine flow tubular sodium transport (TNa). both total delivery TNa were increased, more extracted per transported high-doses HIF-PHIs, suggesting efficiency. Changes RVR GFR nitric oxide (NO) generation substantially suppressed by inhibition synthesis. Conclusions Our data provide mechanistic insights into short-term identify as major mediator these effects.