Project Description

PHD Biology

Acta Physiol (Oxf)). 2021 Apr 26;e13668. doi: 10.1111/apha.13668. Online ahead of print.

Pharmacologic HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.

Burmakin M, Fasching A, Kobayashi H, Urrutia AA, Damdimopoulos A, Palm F, Haase VH.

Abstract

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

Keywords: glomerular filtration rate; hypoxia-inducible factor; molidustat; nitric oxide; prolyl hydroxylase domain; roxadustat.

Introduction

The HIF system plays a major role in the regulation of vascular tone. In the pulmonary vasculature, hypoxia and HIF activation promote the development of pulmonary arterial hypertension through increased expression of vasoconstrictive factors, ion channels and ion transporters, whereas hypoxia and HIF activation in other vascular beds are associated with vasodilation, e.g., in the muscle or skin, promoting blood flow. Little is known about the effects of systemic pharmacologic HIF activation on renal hemodynamics, O2 metabolism and tubular transport efficiency. In this cross-sectional study, we investigated two HIF-PHIs, roxadustat (FG-4592) and molidustat (BAY 85-3934), which have been approved for the treatment of renal anemia in Japan. Our data provide novel insights into the effects of short-term systemic HIF activation on renal hemodynamics and O2 metabolism and identify nitric oxide as a major mediator of these effects.

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see commentary: Get use to the -dustats: Roxadustat and molidustat, members of the hypoxia-inducible factor (HIF) Prolyl hydroxylase (PHD) inhibitor drug class promote kidney function, perfusion and oxygenation in rats through nitric oxide [Acta Physiologica 2021].