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Abstract: TH-PO852

Sodium Glucose Cotransporter 2 Inhibition with Dapagliflozin Confers Renoprotection by Downregulating Megalin in Proximal Convoluted Tubules

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Iida, Tomomichi, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Kuwahara, Shoji, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Hosojima, Michihiro, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Ishikawa, Tomomi, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Wada, Eri, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Kabasawa, Hideyuki, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Goto, Sawako, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Ugamura, Daisuke, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Yoshizawa, Yuta, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Kaseda, Ryohei, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Suzuki, Yoshiki, Niigata University , Niigata, Japan
  • Narita, Ichiei, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • Saito, Akihiko, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
Background

Megalin is an endocytic receptor expressed in the proximal tubules. We found that megalin mediates the endocytosis of glomerular-filtered nephrotoxic proteins, causing high-fat diet (HFD)-induced kidney disease in mice (JASN 2016). Thus, we speculate that appropriate suppression of renal megalin function may delay the development and progression of DKD. Sodium glucose transporter 2 (SGLT2) inhibitors are known to exert renoprotective actions and increase β2-microglobulin, an endocytic ligand of megalin, in urine of patients with type 2 diabetes. Therefore, we studied the effect of dapagliflozin, a widely used SGLT2 inhibitor, on megalin expression in proximal tubular epithelial cells (PTECs).

Methods

Eleven-week-old male C57BL/6J mice, fed a normal fat diet (NFD), were administered 1mg/kg dapagliflozin or vehicle via oral gavage for 7 days; or eight-week-old mice were fed an HFD and administered 1mg/kg dapagliflozin or vehicle for 4 weeks. The effect of dapagliflozin on renal megalin expression was investigated by immunoblotting, quantitative PCR, and immunohistochemistry. Cultured immortalized rat PTECs (IRPTCs) transfected with human SGLT2 cDNA (S-IRPTCs) were treated with 20 μM dapagliflozin or vehicle and evaluated for 2-deoxy-D-glucose uptake and megalin expression.

Results

Dapagliflozin suppressed megalin expression transcriptionally in mice fed either an NFD or HFD. Megalin expression was decreased in the proximal convoluted tubules, but not in the proximal straight tubules. In HFD-fed mice, no difference was noted in blood glucose levels between dapagliflozin and vehicle treatments. Urinary albumin and α1-microglobulin, endocytic ligands of megalin, were increased in dapagliflozin administered mice. In S-IRPTCs treated with dapagliflozin, the expression of both megalin protein and mRNA was decreased in association with decreased glucose uptake.

Conclusion

The renoprotective effect of SGLT2 inhibitors may be at least partly due to megalin downregulation, which would have impacts on the therapeutic strategies with SGLT2 inhibitors including the interpretation of megalin-associated urinary biomarkers in diabetes.