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

Abstract

Background: 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-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. 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.

Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study

“…Tumor cells may produce reactive oxygen species (ROS), and these activate hypoxia-inducible factor 1 alpha (HIF-1a), nuclear factor kappa-B (NFkB), and consequent lactate production in the adjacent fibroblasts, which in turn is associated with faster growth of the cancer cells (40). SGLT2i has been shown to lead to a lower activity of HIF-1a in the kidneys (41)(42)(43). Data regarding the kidneys suggest that hyperglycemia may lead to an abnormal metabolism with high hexokinase and pyruvate kinase M2 activity, low Sirtuin-3 levels, an activated STAT3, and HIF1a signaling and an aberrant glycolysis similar to the Warburg effect in cancer cells.…”

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

“…KEGG pathway enrichment analysis identified that the acetylated proteins identified in our study were localized in a variety of pathways, including TCA cycle, amino acid metabolism, and the HIF-1α pathway. With a wide range of target genes, hypoxia-inducible factor-1 alpha (HIF-1α) has been demonstrated to be involved in EMT under high glucose conditions in renal tubular epithelial cells ( Ndibalema et al, 2020 ). It has been reported that the CREB Binding Protein (CREBBP, P300/CBP, HG/NG: 1.458 fold at K1584, 1.372 fold at K1807) is a common acetyltransferase that can bind to HIF-1α and initiates hypoxia ( Wei et al, 2018 ).…”

Sodium/glucose Co-Transporter 2 Inhibitor, Empagliflozin, Alleviated Transient Expression of SGLT2 after Myocardial Infarction

“…In several previous studies, HIF-1α, TGF-β1, p-SMAD were suggested as regulators of SGLT2. 11) 12) 13) We did additional western blot analyses to confirm the regulation pathway of SGLT2 ( Figure 4C ). The EMPA pre-treated group showed reduced HIF-1α and TGF-β1 expression especially at 72 hr after MI.…”

“… 13) In the hypoxic conditions, HIF-1α was also reported as a regulator of SGLT2, although there are conflicting results whether HIF-1α upregulates. 11) or downregulates SGLT2. 12) We subsequently performed a western blot analysis on such proteins ( Figure 4C ).…”