Role of intrarenal angiotensin-converting enzyme in nephropathy of type II diabetic rats.

To examine the mechanism of nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a recently developed type II diabetic model, we compared the long-term effect of angiotensin-converting enzyme (ACE) inhibitor (imidapril, 1 mg/kg/day), calcium channel blocker (amlodipine, 10 mg/kg/day), and insulin (5-10 U/kg/day) on nephropathy of OLETF rats. Both imidapril and amlodipine, but not insulin, significantly reduced blood pressure of OLETF rats. Imidapril treatment significantly decreased urinary albumin excretions and improved glomerulosclerosis of OLETF rats, while amlodipine failed to improve nephropathy of OLETF rats despite lowering of blood pressure. Insulin treatment, which significantly decreased HbA1c throughout the treatment period, did not ameliorate nephropathy of OLETF rats. Serum ACE activity in OLETF rats was significantly lower than that in genetic control nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. However, glomerular and aortic ACE activities in OLETF rats were significantly higher than those in LETO rats, and were significantly decreased by treatment with imidapril. Furthermore, immunohistochemical analysis of ACE in the kidney using specific antibodies indicated greater ACE immunostaining in the glomeruli and renal vessels of OLETF rats than in those of LETO rats. These observations demonstrate that ACE is involved in the development of nephropathy of OLETF rats and provide evidence that intrarenal ACE rather than circulating ACE may play an important role in nephropathy of this type II diabetic model.