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Abstract: FR-PO419

Inhibition of Glucose Transporters Ameliorates Fibrogenic Signaling in a Cellular Model of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Pan, Xinlu, South West Thames Institute for Renal Research, London, United Kingdom
  • Baines, Deborah L., St George's, University of London, London, United Kingdom
  • Phanish, Mysore K., Epsom and St Helier University Hospitals NHS Trust, London, United Kingdom
  • Dockrell, Mark E., South West Thames Institute for Renal Research, London, United Kingdom

Diabetic Nephropathy (DN) is the leading cause of kidney failure. Prolonged exposure to elevated glucose strongly facilitates the progression of DN. Tubulointerstitial fibrosis is a key prognostic marker of DN. Approximately 90% of glucose in the glomerular ultra-filtrate is reabsorbed by the low affinity Na+/glucose co-transporter SGLT2. Following the advent of therapeutics targeting glucose uptake at this specific site, we propose a role for SGLT2 in regulating DN.


Primary PTEC were grown on collagen IV coated/uncoated culture dishes. On reaching 80% confluence, they were treated with D-Glucose at either 5.5 mM (normoglycaemic control), 25mM (hyperglycaemia) or 5.5 mM D-Glucose + 19.5 mM L-Glucose (osmotic control). Cells were treated with TGFβ1, 0.75ng/ml or vehicle. After 24 h, cells were lysed. Heparin pull down was applied to the media to isolate heparin-binding proteins. Dapagliflozin (0.1, 1 & 10µm) was administered to cells treated with high glucose in combination with TGF-β1. Western blot was then used to detect the level of Connective Tissue Growth Factor (CTGF) and EDA fibronectin protein.


There was no obvious cytotoxic effect of any of the treatments. Western blotting demonstrated that primary PTEC secreted CTGF, mwt 36 & 38kDa. Neither TGF-β1 alone nor raised glucose induced a significant increase in CTGF; however the combination of both did (p<0.05 compared to all other treatments) at 24h. EDA+ fibronectin protein was unchanged. Dapagliflozin at all three concentrations significantly attenuated CTGF protein secretion, reducing the expression to approximately basal levels.


A combination of raised D-Glucose and TGF-β1, similar to that expected in DN, induced a significant increase in CTGF, an important pro-fibrotic marker. Dapagliflozin successfully reduced this outcome, thus confirming SGLT2 function. Interestingly, high glucose and TGF-β1 alone under these conditions did not produce a significant increase in CTGF, suggesting an additive effect in the upregulation of CTGF. Glucose-induced CTGF expression in vascular smooth muscle cells is associated with cellular damage and death. These phenomenon were not observed in our primary renal cells. This suggests a more precise controlled mechanism for glucose-induced CTGF in PTEC.