Abstract: TH-PO672

Amelioration of Kidney Injury by Inhibition of Sodium Glucose Cotransporter 2 with Canagliflozin in Mice with Type 2 Diabetes Mellitus

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Navar, L. Gabriel, Tulane University, New Orleans, Louisiana, United States
  • Satou, Ryousuke, Tulane University Health Science Center, New Orleans, Louisiana, United States
  • Miyata, Kayoko, Tulane University Health Science Center, New Orleans, Louisiana, United States
  • Katsurada, Akemi, Tulane University, New Orleans, Louisiana, United States
  • Dugas, Courtney M, Tulane University, New Orleans, Louisiana, United States
  • Lightell, jr., Daniel J, Tulane University, New Orleans, Louisiana, United States
  • Woods, T Cooper, Tulane University, New Orleans, Louisiana, United States
Background

Type 2 diabetes mellitus (T2DM) is associated with progressively declining renal function resulting from hyperglycemia, oxidative stress and activated intrarenal renin-angiotensin system. The sodium glucose co-transporter 2 (SGLT2) is responsible for most of the glucose reabsorption by renal tubules. SGLT2 inhibitors increase glucose excretion and lower blood glucose levels, thus serving as a new therapy for T2DM. However, their effects on the developing renal injury in T2DM remain unclear.

Methods

Accordingly, we evaluated the ability of canagliflozin (CANA), an SGLT2 inhibitor, to ameliorate kidney injury in T2DM. Intrarenal angiotensinogen (AGT) and oxidative stress were also evaluated as contributing factors to diabetic nephropathy. Male New Zealand Obese mice were fed a regular fat diet (RFD, 4% fat) or a high fat diet (HFD, 40% fat) to induce diabetes. When the mice fed with the HFD exhibited >350 mg/dl blood glucose levels, both RFD and HFD fed mice were treated with 10 mg/kg/day CANA or vehicle for 6 weeks by daily oral gavage.

Results

CANA treatment decreased blood glucose levels and suppressed body weight gain in HFD mice, which remained suppressed for the duration of the study. Systolic blood pressure in HFD groups (134.7±3.6 mmHg) was also normalized by CANA (110.0±6.0 mmHg). The augmented cortical AGT mRNA and protein levels and elevated urinary 8-isoprostane levels caused by the HFD were ameliorated by CANA treatment. Histological analysis revealed the development of renal tubular fibrosis in HFD group (3.4±0.9-fold, fibrotic score, ratio to RFD) that was suppressed by CANA (0.9±0.3-fold). Furthermore, elevated macrophage infiltration into the interstitium caused by HFD was attenuated by CANA (RFD: 0.35±0.07, HFD: 0.99±0.09 and HFD+CANA: 0.49±0.07, positive area %). In contrast, CANA did not improve glomerular matrix expansion and albuminuria observed in the HFD group.

Conclusion

These results demonstrate that CANA mitigates renal tubular fibrosis and renal inflammation accompanied by suppression of renal oxidative stress and AGT expression in T2DM.

Funding

  • Other NIH Support