Abstract 221: Renoprotective Effects of SGLT2 Inhibitor, Luseogliflozin, on the Progression of Diabetic Nephropathy in T2DN Rats
This study examined the effect of long term control of hyperglycemia with a new selective SGLT2 inhibitor, luseogliflozin (TS-071), given alone and in combination with lisinopril on the development of renal injury in a rat model of type 2 diabetic nephropathy (T2DN). Chronic treatment of 14-month old T2DN rats with luseogliflozin (10 mg/Kg/day) reduced plasma glucose levels from 285.7±17.7 mg/dL to 161.7±5.5 mg/dL and HbA1c from 8.9±0.4% to 6.4±0.2% in 17-month old T2DN rats but it had no effect on mean arterial pressure (MAP). Chronic treatment with lisinopril (10 mg/Kg/day) markedly reduced MAP (113.0±4.6 mmHg) compared with 17-month old T2DN rats (140.0±4.1 mmHg) but it had no effect on plasma glucose levels. Combination therapy with luseogliflozin and lisinopril significantly reduced MAP (92.9±4.0 mmHg) more than that seen in lisinopril treated rats. The kidneys of T2DN rats exhibited marked focal glomerulosclerosis with a glomerular injury score of 3.1±0.1 on a 0-4 scale and renal cortical fibrosis of 27.9±0.9%. Control of hyperglycemia with luseogliflozin reduced the glomerular injury score (2.6±0.1) and the renal cortical fibrosis (20.8±0.8%). Reducing blood pressure with lisinopril also reduced the glomerular injury score (2.5±0.1) but not the renal cortical fibrosis (29.0±1.5%). Combination therapy with luseogliflozin and lisinopril markedly reduced the glomerular injury score (2.0±0.1) and the renal cortical fibrosis (15.6±1.0%) more than either drug alone. GFR decreased from 0.44±0.04 to 0.29±0.03 mL/min/g- kwt and RBF decreased from 2.7±0.2 to 2.2±0.2 mL/min/g-kwt in T2DN rats over the course of this study. Chronic treatment of luseogliflozin or lisinopril prevented the decrease of GFR (0.44±0.05 and 0.54±0.05 mL/min/g-kwt) and RBF (3.2±0.2 and 6.7±1.1 mL/min/g-kwt). These results suggest that strict control of blood glucose with the luseogliflozin slows the progression of diabetic nephropathy and combination therapy with luseogliflozin and lisinopril is more effective at lowering blood pressure and is more renoprotective than administration of lisinopril alone.
- © 2012 by American Heart Association, Inc.