Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury

• Published in: PloS one 2016-07, Vol.11 (7), p.e0158810
• Main Authors: Chang, Yoon-Kyung, Choi, Hyunsu, Jeong, Jin Young, Na, Ki-Ryang, Lee, Kang Wook, Lim, Beom Jin, Choi, Dae Eun
• Format: Article
• Language: English
• Subjects: Albendazole; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animal models; Animals; Antidiabetics; Apoptosis; Apoptosis - drug effects; Attenuation; BAX protein; bcl-2-Associated X Protein - metabolism; Benzhydryl Compounds - pharmacology; Biology and Life Sciences; Cell Hypoxia - drug effects; Cell Line; Cell survival; Complications and side effects; Damage assessment; Dapagliflozin; Diabetes; Diabetes mellitus; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Dosage and administration; Dose-Response Relationship, Drug; Drug therapy; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Glucosides - pharmacology; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-inducible factors; Inhibition; Inhibitors; Injury prevention; Ischemia; Kidney diseases; Kidney Diseases - drug therapy; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Kinases; Liver; Male; Medicine; Medicine and Health Sciences; Mice; Nephrology; Oxidative stress; Oxygen; Physical Sciences; Physiology; Proteins; Renal function; Reperfusion; Reperfusion injury; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Rodents; Sodium; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Survival; Transplants & implants
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158810

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.