Abstract P464: Sodium Glucose Cotransporter 2 Inhibition by Canagliflozin Attenuates Intrarenal Angiotensinogen Augmentation in Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a complex disease where hyperglycemia occurs as a result of the development of insulin resistance. T2DM leads to complications, including renal and cardiovascular injury. Renal proximal tubular angiotensinogen (AGT) is stimulated by hyperglycemia via elevated oxidative stress, and is associated with activation of the intrarenal renin-angiotensin system which contributes to development of high blood pressure and diabetic nephropathy in diabetes mellitus. Sodium glucose co-transporter 2 (SGLT2) is mainly expressed in early renal proximal tubules and is responsible for most of the glucose reabsorption by the tubules. This study tested the effects of canagliflozin (CANA), an SGLT2 inhibitor, on intrarenal AGT regulation in T2DM mice. 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 HFD exhibited >350 mg/dl blood glucose levels (week 0), both RFD and HFD fed mice were treated with 10 mg/kg/day CANA or vehicle for 6 weeks by daily oral gavage. Systolic blood pressure (SBP) levels were measured by a tail cuff system and 24-hour urine samples were collected using metabolic cages. Intrarenal AGT mRNA and protein levels were determined by digital PCR and western blot analysis. CANA treatment decreased blood glucose levels in HFD mice, which remained suppressed for duration of the study. SBP in HFD groups were higher than in the RFD and RFD+CANA groups (134.7±3.6, 118.7±10.8 and 108.3±7.6 mmHg) at week 6. The elevated SBP was normalized by CANA (110.0±6.0 mmHg). The HFD group exhibited greater renal cortical AGT mRNA levels than the RFD group (3.7±0.4 vs. 7.4±1.0 copies/reaction). Likewise, intrarenal AGT mRNA expression was lower in CANA treated group (4.5±0.8 copies/reaction). Western blot analysis also showed lower AGT protein levels in CANA treated group (1.02±0.08-fold compared with RFD) than in HFD group (1.49±0.08-fold). In the HFD group, CANA treatment also suppressed elevated urinary 8-isoprostane levels, a marker of renal oxidative stress. These results demonstrate that CANA attenuates intrarenal AGT augmentation that occurs in T2DM, which may mitigate the development of diabetic nephropathy and progression of high blood pressure.