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Abstract: TH-PO853

SGLT2 Inhibition Relieves High Glucose-Induced Metabolic Disorders in Tubular Epithelial Cells Through Regulation of HIF-1α Pathway

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Cai, Ting, Nanjing Medical University, Nanjing, JIANGSU , China
  • Zhou, Yang, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
  • Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
Background

SGLT2 inhibitor (SGLT2i) has been proved to be renoprotective by reducing hyperperfusion, hyperfiltration and hypertension in glomeruli of diabetic kidney. However, high concentration of glucose reabsorbed into proximal tubular cells induced consequence abnormalities in glucose and lipid metabolism seems to be detrimental in diabetic kidney disease (DKD). In this study, we examined whether SGLT2i dapagliflozin may rectify metabolic disorders and explore the possible mechanism.

Methods

Diabetic model was induced by streptozotocin injection. Losartan was used as hemodynamic control. Dapagliflozin and losartan were given by oral gavage for 12 weeks. Mice were randomly assigned into six groups as follows: control + vehicle, control + dapagliflozin (5mg/kg), control + losartan (10mg/kg), diabetes + vehicle, diabetes + dapagliflozin (5mg/kg), diabetes + losartan (10mg/kg). High glucose-incubated primary tubular cells (PTCs) were treated with or without dapagliflozin for indicated time periods.

Results

In both diabetic kidney and glucose-treated PTCs, metabolic abnormalities were notable as demonstrated by increased lactate level and lipid accumulation accompanied with increased expression of enzymes for glycolysis and decreased expression of enzymes for fatty acid oxidation. Dapagliflozin treatment decreased blood glucose level, attenuated the increase of kidney/body weight ratio, albuminuria excretion rate, urinary NGAL level and tubulointerstitial fibrosis. Furthermore, dapagliflozin treatment relieved the increase of lactate level and accumulation of lipid droplet in tubular cells. The increased expression of glycolytic enzymes and decreased expression of fatty acid enzymes were rectified by dapagliflozin. These metabolic benefits were not observed in losartan-treated group. Moreover, expression of HIF-1α, the regulator of metabolism was increased, which suggested the stabilization of HIF-1α in diabetic kidney. Nevertheless, dapapagliflozin treatment inhibited HIF-1α stabilization. HIF-1α stabilizer BAY85-3934 blocked the protective role of dapagliflozin on metabolism in high glucose-treated PTCs.

Conclusion

We suggested that SGLT2 inhibitor protects against metabolic abnormalities and relieves tubular damage in diabetes through HIF-1α pathway.

Funding

  • Government Support - Non-U.S.