Diabetes, Metabolic Syndrome and Obesity (Jun 2020)
Empagliflozin Protects Against Proximal Renal Tubular Cell Injury Induced by High Glucose via Regulation of Hypoxia-Inducible Factor 1-Alpha
Abstract
Angelamellisy Revelian Ndibalema,1,2 Deo Kabuye,3,4 Si Wen,1 Lulu Li,1 Xin Li,1 Qiuling Fan1 1Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Kairuki Hospital, Dar es Salaam, Tanzania; 3Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 4Kalisizo Hospital Uganda, Kalisizo, UgandaCorrespondence: Qiuling Fan Tel +86 13904012680Email [email protected]: 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).Materials and Methods: 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.Results: High glucose (HG) increased expression of Collagen IV, Fibronectin, transforming growth factor-beta1 (TGF-β 1). However, emp treatment remarkably decreased expression of TGF-β 1, 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.Conclusion: 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.Keywords: humans, animals, transforming growth factor-beta1, empagliflozin, diabetic nephropathies, glucose
