Abstract: FR-PO591

SGLT2 Inhibitor Dapagliflozin Is Renoprotective in Streptozotocin-Induced Diabetes

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Balogh, Dora Bianka, MTA-SE Lendület Diabetes Research Group, Budapest, Hungary
  • Lenart, Lilla, MTA-SE Lendület Diabetes Research Group, Budapest, Hungary
  • Hodrea, Judit, MTA-SE Lendület Diabetes Research Group, Budapest, Hungary
  • Hosszu, Adam, MTA-SE Lendület Diabetes Research Group, Budapest, Hungary
  • Vannay, Ádám, Semmelweis University, Budapest, Hungary
  • Wagner, Laszlo J., Semmelweis University, Budapest, Hungary
  • Szabo, Attila J., Semmelweis University, Budapest, Hungary
  • Fekete, Andrea, MTA-SE Lendület Diabetes Research Group, Budapest, Hungary
Background

Inhibitors of sodium-glucose co-transporter 2 (SGLT2) are a new class of antihyperglycemic drugs that act by inhibiting SGLT2 mediated glucose reabsorption in the proximal tubules. They have recently been approved type 2 diabetes, however their use is limited in renal impairment. They have not been registered yet in type 1 diabetes (T1DM) either. Previously we showed that in diabetic kidney injury activity of the hexosamine biosynthesis pathway is increased, resulting in protein O-linked N-acetylglucosamine modification (O-GlcNAcylation), which induces cellular processes leading to the progression of renal failure. The dynamic addition (by OGT) and removal (by OGA) of O-GlcNAc modulates signaling molecules which results in kidney fibrosis.
Since there is still an unmet need for oral therapies in T1DM here we investigated the antidiabetic and possibly renoprotective effect of the highly selective SGLT2 inhibitor dapagliflozin (DAPA) in streptozotocin-induced model of DM.

Methods

T1DM was induced by streptozotocin (65 mg/bwkg, ip.) in male Wistar rats. Immediately following onset of DM the animals were treated per os for six weeks with DAPA (D+DAPA, 1 mg/bwkg/day). Metabolic, renal parameters and kidney histology was evaluated. Specific markers of tubular damage (NGAL, KIM-1), profibrotic factors (CTGF, PDGF, TGF-β), proinflammatory cytokines (IL-6, IL-1β, TNF-α) and α-SMA, O-GlcNAc, OGT and OGA protein levels were measured.

Results

Development of diabetic kidney injury was confirmed by impairment of renal function, massive proteinuria and structural damage of kidneys. DAPA reduced weight loss and decreased blood glucose level. DAPA Treatment improved GFR, ameliorated tubular damage and decreased of proinflammatory cytokines IL-6, IL-1β, TNF-α and profibrotic growth factors CTGF, PDGF, TGF-β. SGLT2 inhibition ameliorated DM-induced mesangial matrix expansion and tubulo-interstitial fibrosis. DM-induced elevated proteins O-GlcNAcylation, OGT, OGA and α-SMA levels were reduced by DAPA.

Conclusion

DAPA improved metabolic and renal parameters and decreased the histological lesions in the kidney. Decrease of O-GlcNAcylation by DAPA has a beneficial effect on profibrotic processes. These results support the effective and safe clinical application of DAPA in the prevention/treatment of T1DM and associated nephropathy.