Abstract: TH-OR131

Comprehensive Renoprotective Mechanisms of Ipragliflozin against Diabetic Nephropathy

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Kamezaki, Michitsugu, Kyoto Chubu Medical Center, Nantan, Japan
  • Kusaba, Tetsuro, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Yamashita, Noriyuki, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Uehara, Masahiro, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Tamagaki, Keiichi, Kyoto Prefectural University of Medicine, Kyoto, Japan
Background

Clinical and experimental investigations showed that sodium glucose co-transporter 2 inhibitors (SGLT2i) potentiate glucose-lowering and natriuretic effects and contribute to the prevention of diabetic kidney disease progression. Amelioration of glomerular hyperfiltration is one of the candidate, but the other molecular mechanisms are not fully understood.

Methods

To distinguish these different pharmacological effects on the molecular mechanisms underlying the development of diabetic kidney disease, we administered different doses of SGLT2i, ipragliflozin, (low dose: Ipra-LD, high dose: ipra-HD or vehicle) into type 2 diabetic, db/db mice for 8weeks through oral gavage.

Results

Though body fluid volume was depleted in both Ipra-LD and Ipra-HD, only high dose Ipra significantly lowered blood glucose and reduced urinary albumin excretion. 3-nitrotyrosine (3-NT) immunostaining demonstrated that oxidative stress in the kidney was ameliorated by Ipra at dose-dependent manner. qPCR showed that expressions of tubular injury marker and NADPH oxidase 4 (Nox4) was improved in both Ipra-LD and Ipra-HD. Electron microscopy showed that Ipra improved the diabetes induced-abnormal mitochondrial cristae formation. Regarding kidney hypoxia, pimonidazole immunostaining showed that both high and low dose Ipra ameliorated the tubular hypoxia in the renal cortex where SGLT2i act. Regarding glomerulus, increased glomerular area in diabetic kidney reflecting hyperfiltration was ameliorated by both Ipra-LD and -HD. 3-NT immunostaining in glomerulus demonstrated the dose-dependent amelioration of oxidative stress in podocyte by Ipra. We further assessed the molecular mechanisms by using a glomeruli isolation technique, and found that high dose ipra preserved podocyte markers and reduced Nox4 expressions.

Conclusion

We verified the dose-dependent difference in the effect of ipra on diabetic nephropathy in vivo. Especially even low dose ipra improved the renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, high dose ipra exhibited renoprotective effects through the reduction of oxidative stress in both tubular epithelia and glomerular podocytes.