title: Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury.
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.
authors.affiliation: Department of Nephrology, Daejeon St. Mary Hospital, Daejeon, South Korea.|Department of Nephrology, Catholic University of Korea, Seoul, South Korea.
authors.forename: Yoon-Kyung
authors.initials: YK
authors.lastname: Chang
authors.affiliation: Clinical Research Institute, Daejeon St. Mary Hospital, Daejeon, South Korea.
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Nephrology, School of medicine, Chungnam National University, Daejeon, South Korea.|Department of Medical Science, School of medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Department of Nephrology, School of medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: Ki-Ryang
authors.initials: KR
authors.lastname: Na
authors.affiliation: Department of Nephrology, School of medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: Kang Wook
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of pathology, College of medicine, Yeonse University, Seoul, South Korea.
authors.forename: Beom Jin
authors.initials: BJ
authors.lastname: Lim
authors.affiliation: Department of Nephrology, School of medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: Dae Eun
authors.identifier: http://orcid.org/0000-0003-2870-3958
authors.initials: DE
authors.lastname: Choi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D001559:Benzhydryl Compounds; D005960:Glucosides; D051793:Hypoxia-Inducible Factor 1; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D051028:bcl-2-Associated X Protein; C529054:dapagliflozin; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases