Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage.

Abstract

Hypoxia-inducible factor (HIF) mediates protection via hypoxic preconditioning in both, in vitro and in vivo ischemia models. However, the underlying mechanism remains largely unknown. Prolyl hydroxylase domain proteins serve as the main HIF regulator via hydroxylation of HIFα leading to its degradation. At present, prolyl hydroxylase inhibitors including enarodustat are under clinical trials for the treatment of renal anemia. In an in vitro model of ischemia produced by oxygen-glucose deprivation of renal proximal tubule cells in culture, enarodustat treatment and siRNA knockdown of prolyl hydroxylase 2, but not of prolyl hydroxylase 1 or prolyl hydroxylase 3, significantly increased the cell viability and reduced the levels of reactive oxygen species. These effects were offset by the simultaneous knockdown of HIF1α. In another in vitro ischemia model induced by the blockade of oxidative phosphorylation with rotenone/antimycin A, enarodustat-enhanced glycogen storage prolonged glycolysis and delayed ATP depletion. Although autophagy is another possible mechanism of prolyl hydroxylase inhibition-induced cytoprotection, gene knockout of a key autophagy associated protein, Atg5, did not affect the protection. Enarodustat increased the expression of several enzymes involved in glycogen synthesis, including phosphoglucomutase 1, glycogen synthase 1, and 1,4-α glucan branching enzyme. Increased glycogen served as substrate for ATP and NADP production and augmented reduction of glutathione. Inhibition of glycogen synthase 1 and glutathione reductase nullified enarodustat's protective effect. Enarodustat also protected the kidneys in a rat ischemia reperfusion injury model and the protection was partially abrogated by inhibiting glycogenolysis. Thus, prolyl hydroxylase inhibition protects the kidney from ischemia via upregulation of glycogen synthesis.

• Authors: Marie Ito, Tetsuhiro Tanaka, Taisuke Ishii, Takeshi Wakashima, Kenji Fukui, Masaomi Nangaku
• Journal: Kidney international (Kidney Int) Vol. 97 Issue 4 Pg. 687-701 (04 2020) ISSN: 1523-1755 [Electronic] United States
• PMID: 32033782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• N-substituted Glycines
• Pyridines
• Triazoles
• Glycogen
• Prolyl Hydroxylases
• enarodustat

Topics

• Animals
• Glycogen
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Ischemia
• Kidney (metabolism)
• N-substituted Glycines
• Prolyl Hydroxylases (metabolism)
• Pyridines
• Rats
• Triazoles
• Up-Regulation