The purpose of this project is to identify treatments to prevent or slow the rate of progression of renal disease in type 2 diabetes mellitus in the Pima Indians. The efficacy of the angiotensin-converting-enzyme inhibitor (ACEi) lisinopril is being tested in 20 Pima Indians with overt diabetic kidney disease. Glomerular function was measured in each subject for about 4 years prior to treatment with lisinopril and it will be measured at 6-monthly intervals during treatment. Measurements of glomerular function will continue until the onset of renal failure, and changes in glomerular function before and after initiation of lisinopril treatment will be examined. A randomized, double-blinded, placebo-controlled clinical trial is being conducted in 170 diabetic Pima Indians with normal urinary albumin excretion or microalbuminuria to determine whether blockade of the angiotensin II receptor with losartan will prevent or attenuate the development and progression of early diabetic nephropathy. Kidney biopsies will be performed after 5.5 years in all subjects. Morphometric analysis of kidney biopsies will be used to determine differences in the prevalence of global sclerosis, the number of visceral epithelial cells per glomerulus, and the breadth of epithelial foot processes between treatment groups. Differences in a severity index computed from the joint distribution of these morphometric variables will be used to assess the renoprotective efficacy of losartan at the tissue level. Particular attention will be paid to podocyte biology, since loss of podocytes appears to be an important factor in the progression of kidney disease in diabetes. Treatment will continue until subjects reach the primary endpoint, a GFR of 60 ml/min or less or a decline in GFR to half the baseline value in those that entered the study with a GFR of less than 120 ml/min. The trial will end prior to reaching the primary endpoint if there is sufficient evidence to draw conclusions regarding the renoprotective efficacy of losartan based on the morphometric analysis of the kidney biopsy specimens. These projects, in part, represent extensions of work previously reported as Project Number Z01 DK 69037.