Angiotensin converting enzyme (ACE), a carboxyl-peptidase that converts the inactive precursor angiotensin linto the active angiotesion II, plays a crucial role in the development and progression of diabetic nephropathy. Randomized, double blinded clinical trials demonstrate the efficacy of ACE inhibitors in preventing and ameliorating diabetic nephropathy. Part of the benefit from ACE inhibition in slowing the progression of diabetic nephropathy arises from the reduction of blood pressure. However, the beneficial effect of ACE inhibitors may be greater than that of other classes of antihypertensive medications (titrated to the same blood pressure. Despite the beneficial effects of ACE inhibitors, the activity of the systemic renin/angiotensin system in diabetes is not chronically increased: plasma levels of rennin, angiotensinigen and angiotensin II are either suppressed or unchanged in diabetes. Individual organs, including the kidney, also contain all components of the renin/angiotensin system. There is apparent regulation of the local renal renin/angiotensin system during diabetes mellitus especially in the glomerulus: glomerular ACE protein increases markedly in both animal models and human diabetic. This activated glomerular rennin/angiotensin system could produce the angiotensin II that causes glomerular damage in diabetic nephropathy. Our hypothesis is that intrinsic renal ACE activity generates the angiotensin II which causes the renal damage in diabetic nephropathy. There have been no well-defined studies separating the relative roles of kidney and systemic renin/angiotensin systems in diabetic nephropathy. In this pilot application, we propose to address this issue using transgenic mice with normal circulating ACE, but decreased ACE expression in the kidney (ACE.3 mice). Our goals are to characterize the renin/angiotensin system in diabetic mice deficient in renal ACE and to determine if mice deficient in renal ACE develop glomerular damage in response to diabetes mellitus. We will examine if markers of kidney damage, such a collagen expression and transforming growth factor expression as well as proteinuria are altered by lack of renal ACE. We believe that this approach will not only critically test our hypothesis, but will also lay the ground work for future studies into the role of ACE in the diabetic kidney.