Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics.

Abstract

Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure, or glomerular filtration pressures. Their effects to promote erythrocytosis suggest that these drugs act on hypoxia-inducible factors (HIFs; specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α and thereby augment erythropoiesis, while muting organellar dysfunction, inflammation, and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney.

• Authors: Milton Packer
• Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation (Am J Kidney Dis) Vol. 77 Issue 2 Pg. 280-286 (02 2021) ISSN: 1523-6838 [Electronic] United States
• PMID: 32711072 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Sodium-Glucose Transporter 2 Inhibitors
• endothelial PAS domain-containing protein 1
• Cobalt
• cobaltous chloride

Topics

• Basic Helix-Loop-Helix Transcription Factors (drug effects, metabolism)
• Cobalt (pharmacology)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Diabetic Nephropathies (drug therapy, metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Erythropoiesis (drug effects)
• Fibrosis
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (drug effects, metabolism)
• Inflammation
• Kidney (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Signal Transduction (drug effects)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)