Elucidating novel mechanisms in the pathogenesis of Alport syndrome

PROJECT ABSTRACT Alport syndrome is the second most common cause of hereditary chronic kidney disease and is caused by mutations in the type IV collagen genes encoding α3, α4 and α5 chains. X-linked Alport syndrome (XLAS) accounts for most cases and is caused by mutations of the α5 chain. Therapies to slow the progression of XLAS are limited and affected males invariably progress to end stage kidney disease. The disease is known to affect glomeruli: the α3, α4 and α5 (IV) chains are deposited by podocytes into the glomerular basement membrane, and patients with Alport syndrome have structural defects in the glomerular basement membrane that causes hematuria and proteinuria. Despite this, there are major gaps in our understanding of disease pathogenesis. It is known that other cell types in the kidney produce α3, α4 and α5 chains, but to date, their function and the role they play in tubule function and disease pathogenesis has been unexplored. Based on preliminary studies, we hypothesize that α5 from non-glomerular cells is required for normal cell function and shape, and that the non-glomerular cell abnormalities contribute substantially to the clinical presentation and pathogenesis of XLAS. We therefore propose to 1) identify the glomerular and non-glomerular contributions to XLAS pathogenesis and progression, 2) establish the function(s) of α5 in tubular cells, including elucidating signaling pathways that underlie its role in tubular cells. Together, these studies will generate resources to study type IV collagen function and will greatly advance knowledge of the pathogenesis of XLAS. We expect they may also pave the way for future studies that lead to the development of novel therapeutic strategies.