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

Jinpeng Li,Daisuke Koya,Susumu Takagi,Munehiro Kitada,Keizo Kanasaki,Swayam Prakash Srivastava,Haijie Liu,Yuta Takagaki,Kyoko Nitta

doi:10.1172/jci.insight.129034

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors are beneficial in halting diabetic kidney disease; however, the complete mechanisms have not yet been elucidated. The epithelial-mesenchymal transition (EMT) is associated with the suppression of sirtuin 3 (Sirt3) and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor empagliflozin restores normal kidney histology and function in association with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis that was associated with the EMT at 4 months after diabetes induction. Empagliflozin intervention for 1 month restored all pathological changes; however, adjustment of blood glucose by insulin did not. Empagliflozin normalized the suppressed Sirt3 levels and aberrant glycolysis that was characterized by HIF-1α 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.

Highlights

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, but a specific therapy to halt the progression of DKD is not available [1]
We described the potential renoprotective effects of empagliflozin via suppression of the epithelial-mesenchymal transition (EMT) in the kidney proximal tubule
In the proximal tubule in a manner that was associated with suppression of HIF-1α and phosphorylated STAT3 (P-STAT3), pyruvate kinase M2 (PKM2) dimer formation and aberrant glycolysis; (d) Sodium glucose cotransporter 2 (SGLT2) knockdown in HK2 cells resulted in protection from high-glucose medium–induced EMT in association with suppression of aberrant glycolysis similar to that of the in vivo model; and (e) conditioned medium from SGLT2-knockdown HK2 cells protected human dermal microvascular endothelial cells (HMVECs) from the endothelial-mesenchymal transition (EndMT)

Summary

Introduction

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, but a specific therapy to halt the progression of DKD is not available [1]. There is a significant demand in diabetes research for additional or alternative strategies to combat DKD progression. SGLT2 plays a significant role in the reabsorption of glucose filtered from the glomerulus [4]. 90%–95% of filtered glucose in the urine is taken up through SGLT2. The function of SGLT2 in glucose reabsorption and the lack of significant health problems in patients with renal glycosuria who have mutations in the SGLT2 gene have led researchers to develop an SGLT2 inhibitor as an antidiabetic drug that expels glucose into the urine [4]

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Results

Conclusion