COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps

<i>Background</i>: COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney diseases, myopathies with cramps, and heritable intracranial aneurysms remain unknown.<p></p> <i>Methods</i>: We characterized the renal and extrarenal phenotypes of subjects from three families who had an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), which we propose is a syndrome. Linkage studies involving microsatellite markers flanking the COL4A1–COL4A2 locus were performed, followed by sequence analysis of COL4A1 complementary DNA extracted from skin-fibroblast specimens from the subjects.<p></p> <i>Results</i>: We identified three closely located glycine mutations in exons 24 and 25 of the gene COL4A1, which encodes procollagen type IV 1. The clinical renal manifestations of the HANAC syndrome in these families include hematuria and bilateral, large cysts. Histologic analysis revealed complex basement-membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appears to affect both small vessels and large arteries.<p></p> <i>Conclusions</i>: COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.<p></p&gt

Modification of kidney barrier function by the urokinase receptor

9 páginas, 5 figuras, 1 tabla -- PAGS nros. 55-63Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of v3 integrin. Mice lacking uPAR (Plaur- /- ) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active 3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate v3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of v3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeabilityThis work was supported by US National Institutes of Health (NIH) grants DK073495 (to J.R.), DK057683, DK062472 and the George M. O'Brien Kidney Center DK064236 (to P.M.). C.W. is the Halpin Scholar of the American Society of Nephrology. C.C.M. was supported by a scholarship of the German Academic Exchange Service. M.M.A. was supported by NIH training grant T32DK007540. Gene expression studies of uPAR in human disease were performed in the framework of the European renal cDNA bank. We thank all members of the European Renal cDNA Bank and their patients for their support (for participating centers at the time of the study, see ref. 26). Part of the electron microscopy work was performed in the Microscopy Core facility of the Massachusetts General Hospital Program in Membrane Biology and was supported by an NIH Program Project grant (DK38452)Peer reviewe