Alport syndrome is an inherited form of kidney disease, associated with deafness, that results from genetic abnormalities in type IV collagen, an integral component of tissue structures known as basement membranes. In most families with Alport syndrome the disease is transmitted as an X-linked dominant condition, and affected males develop kidney failure in adolescence or young adulthood. While much has been learned recently about the genetics of Alport syndrome, the mechanisms by which the disease progresses inexorably to kidney failure are not understood. There is currently no treatment for Alport kidney disease, other than renal transplantation. Kidney disease that is indistinguishable genetically, biochemically and pathologically from Alport syndrome occurs spontaneously in some dog families. These dogs provide the opportunity to test potential therapeutic interventions in Alport syndrome, and also to elucidate the pathogenesis of renal failure in this disease. The studies proposed in this application are based on the following hypotheses: (1) renal failure in Alport syndrome results from accumulation of particular collagen types in the kidney, initiated by the primary genetic defect and driven by TGF-b1; and (2) inhibition of angiotensin converting enzyme can slow the rate of progression to renal failure, by suppressing TGF-b1 activity and consequently the accumulation of collagen in the kidney. Hypothesis #1 will be tested by performing serial renal biopsies in affected male members of a dog family with hereditary nephritis (so-called """"""""Navasota dogs""""""""). The extent of collagen accumulation and TGF-b1 expression in these biopsies will be assessed by immunohistology, immunoelectron microscopy and messenger RNA studies (in situ hybridization and quantitative polymerase chain reaction). These measurements will be correlated with indices of renal function (glomerular filtration and proteinuria) and renal stuctural alterations (percent glomerular sclerosis, mesangial volume fraction, glomerular basement membrane thickness and splitting, and cortical interstitial volume fraction). Hypothesis #2 will be tested by comparing affected male dogs treated from the first month of life with an inhibitor of angiotensin converting enzyme (enalapril) to dogs that receive no such treatment. Comparisons will focus on the rates of change in measures of renal function, renal scarring, and collagen and TGF-b1 expression in the kidneys.
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