Empagliflozin Protects Against Proximal Renal Tubular Cell Injury Induced by High Glucose via Regulation of Hypoxia-Inducible Factor 1-Alpha

• Published in: Diabetes, metabolic syndrome and obesity metabolic syndrome and obesity, 2020-01, Vol.13, p.1953-1967
• Main Authors: Ndibalema, Angelamellisy Revelian, Kabuye, Deo, Wen, Si, Li, Lulu, Li, Xin, Fan, Qiuling
• Format: Article
• Language: English
• Subjects: Angiotensin II; animals; Antidiabetics; Bone morphogenetic proteins; Canagliflozin; Collagen; Dapagliflozin; Diabetes; Diabetic nephropathies; Empagliflozin; Fibronectins; Glucose; humans; Hyperglycemia; Hypertension; Hypoxia; Kidney diseases; Muscle proteins; Original Research; Proteins; Stem cells; transforming growth factor beta1; Transforming growth factors; Type 2 diabetes; Urine
• ISSN: 1178-7007; 1178-7007
• DOI: 10.2147/DMSO.S243170

Evidence from both animal and human studies clearly supports the renal beneficial effects of empagliflozin (emp), a sodium glucose co-transporter 2 (SGLT2) inhibitor, but the mechanism in which it exerts its effect is not well understood. In this study, we investigated the capability of emp on reducing hyperglycemia-induced renal proximal tubular epithelial cells injury and we evaluated if the renoprotective effect of emp associates with hypoxia-inducible factor-1α (HIF-1α). Human kidney cell lines (HK-2 cells) were incubated in normoxia, high glucose with or without emp treatment for 72 hours to evaluate the induction of HIF-1α, glucose transporter-1, SGLT2, the fibrosis signal pathway and epithelial-mesenchymal transition (EMT) markers. High glucose (HG) increased expression of Collagen IV, Fibronectin, transforming growth factor-beta1 (TGF-β1). However, emp treatment remarkably decreased expression of TGF-β1, accumulation of extracellular matrix proteins (Fibronectin, Collagen IV), as well as (phosphorylated-smad3) P-smad3. HG increased SGLT2 protein expression compared to normal glucose (NG) while emp significantly decreased SGLT2 expression. Furthermore, emp decreased high glucose-induced alpha-smooth muscle actin (α-SMA) expression and reversed epithelial marker (E-catherin) suppression induced by high glucose. In addition, emp treatment for 72 h increased expression of HIF-1α protein (95% CI: -0.5918 to -0.002338, at 100nM, P < 0.05, 95% CI -0.6631 to -0.07367 at 500nM, P < 0.05) in hyperglycemic normoxic HK-2 cells. Furthermore, we observed increased expression of GLUT-1 protein after emp treatment and remarkably decreased cell proliferation. Emp treatment protected proximal renal tubular cells injury induced by high glucose. Induction of HIF-1α expression by emp may play an essential role in the protection of high glucose-induced proximal renal tubular epithelial cells injury.