Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury

PLoS One. 2016 Jul 8;11(7):e0158810. doi: 10.1371/journal.pone.0158810. eCollection 2016.

Abstract

Dapagliflozin, a new type of drug used to treat diabetes mellitus (DM), is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although some studies showed that SGLT2 inhibition attenuated reactive oxygen generation in diabetic kidney the role of SGLT2 inhibition is unknown. We evaluated whether SLT2 inhibition has renoprotective effects in ischemia-reperfusion (IR) models. We evaluated whether dapagliflozin reduces renal damage in IR mice model. In addition, hypoxic HK2 cells were treated with or without SGLT2 inhibitor to investigate cell survival, the apoptosis signal pathway, and the induction of hypoxia-inducible factor 1 (HIF1) and associated proteins. Dapagliflozin improved renal function. Dapagliflozin reduced renal expression of Bax, renal tubule injury and TUNEL-positive cells and increased renal expression of HIF1 in IR-injured mice. HIF1 inhibition by albendazole negated the renoprotective effects of dapagliflozin treatment in IR-injured mice. In vitro, dapagliflozin increased the expression of HIF1, AMP-activated protein kinase (AMPK), and ERK and increased cell survival of hypoxic HK2 cells in a dose-dependent manner. In conclusion, dapagliflozin attenuates renal IR injury. HIF1 induction by dapagliflozin may play a role in renoprotection against renal IR injury.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Apoptosis / drug effects
  • Benzhydryl Compounds / pharmacology*
  • Cell Hypoxia / drug effects
  • Cell Line
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glucosides / pharmacology*
  • Hypoxia-Inducible Factor 1 / metabolism
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Bax protein, mouse
  • Benzhydryl Compounds
  • Glucosides
  • Hypoxia-Inducible Factor 1
  • Slc5a2 protein, mouse
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • bcl-2-Associated X Protein
  • dapagliflozin
  • Extracellular Signal-Regulated MAP Kinases
  • AMP-Activated Protein Kinases

Grant support

This work was supported by a Clinical Research Institute grant (CMCDJ-A-2015–020) funded by The Catholic University of Korea Daejeon St. Mary’s Hospital. This study was supported by a faculty research grant of Yonsei University College of Medicine for 2009 (6-2009-0103). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.