Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules

2020 
SGLT2 inhibitors are beneficial in halting diabetic kidney disease; complete mechanisms is unknown. The epithelial to mesenchymal transition (EMT) is associated with Sirt3 suppression and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor restores normal kidney histology/function associated with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis associated with the EMT at 4-months after diabetes induction. Empagliflozin intervention for one month restored all changes; adjustment of blood glucose by insulin did not. Empagliflozin normalized suppressed Sirt3 levels and aberrant glycolysis (characterized by hypoxia-inducible factor-1alpha accumulation, hexokinase 2 induction and pyruvate kinase isozyme M2 dimer formation) in diabetic kidneys. Empagliflozin also suppressed the accumulation of glycolysis byproducts in diabetic kidneys. Another SGLT2 inhibitor, canagliflozin, demonstrated similar in vivo effects. High-glucose media induced the EMT, which was associated with Sirt3 suppression and aberrant glycolysis induction, in the HK2 proximal tubule cell line; SGLT2 knockdown suppressed the EMT with restoration of all aberrant functions. SGLT2 suppression in tubular cells also inhibited the mesenchymal transition of neighboring endothelial cells. Taken together, SGLT2 inhibitors exhibit renoprotective potential that is partially dependent on the inhibition of glucose reabsorption and subsequent aberrant glycolysis in kidney tubules.
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