PS 10-03 EFFECTS OF LCZ696 ON BLOOD PRESSURE AND RENAL INJURY IN TYPE 2 DIABETIC RATS WITH OVERT PROTEINURIA

Abstract

Objective: Clinical studies have indicated that LCZ696, an angiotensin receptor-neprilysin inhibitor, exerts beneficial effects in patients with heart failure. Here, we aimed to examine the effect of LCZ696 on blood pressure and renal injury in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats with overt proteinuria. Design and Method: In OLETF rats, vehicle (n = 10), valsartan (30 mg/kg/day, n = 10), LCZ696 (68 mg/kg/day, n = 9) or valsartan plus hydralazine (3 mg/kg/day, n = 10) was treated from 56 to 80 weeks of age. Results: At baseline (56-week-old), diabetic OLETF rats showed hypertension, overt proteinuria, glomerular injury (glomerular PAS positive area) and tubulointerstitial fibrosis (Sirius Red-positive area). At 80-week-old, vehicle-treated OLETF rats showed developed hypertension and proteinuria, severe glomerular injury and tubulointerstitial fibrosis, and increases in plasma BUN and creatinine levels. Treatment with LCZ696 or valsartan plus hydralazine similarly caused greater blood pressure reduction than valsartan. On the other hand, LCZ696 caused greater reductions in proteinuria, glomerular injury and tubulointerstitial fibrosis than valsartan or valsartan plus hydralazine. LCZ696 also prevented the increases in plasma BUN and creatinine levels. Conclusions: These data suggest that LCZ696 elicits a reno-protective effect in type 2 diabetes with hypertension and nephrotic-range proteinuria.