%0 Generic
%A Möller, Clemens Claudius
%D 2007
%F heidok:7728
%K PodozytTRPC6
%R 10.11588/heidok.00007728
%T Role of the Transient Receptor Potential Canonical 6 ion channel in genetic and acquired forms of proteinuric kidney disease
%U https://archiv.ub.uni-heidelberg.de/volltextserver/7728/
%X Podocyte foot processes and the interposed glomerular slit diaphragm are critical components of the permeability barrier in the kidney. Mutations in several podocyte genes have been identified as the cause for progressive kidney failure and focal segmental glomerulosclerosis (FSGS). Podocyte injury is a hallmark of glomerular disease and usually involves the rearrangement of the podocyte actin cytoskeleton. Cell-specific therapies targeting podocyte injury are currently not available. In 2004, a mutation in the TRPC6 ion channel was found to cosegregate with hereditary FSGS. Based on this finding it was hypothesized that TRPC6 is expressed in podocytes, and that TRPC6-mediated Ca2+ signaling contributes to the regulation of the podocyte actin cytoskeleton. According to this model, dysfunction of TRPC6 leads to a disruption of normal cytoskeletal organization, podocyte injury, and proteinuric disease. To test this hypothesis, four specific aims were outlined. First, to explore TRPC6 mutations in genetic FSGS. Second, to investigate its association with the glomerular filtration barrier. Third, to study TRPC6 expression in acquired forms of proteinuric kidney disease. Fourth, to investigate the molecular basis of TRPC6 contribution to the pathophysiology of proteinuric kidney disease In genetic forms of FSGS, additional TRPC6 mutations were identified in five families with a history of FSGS. TRPC6-related FSGS presented as a late-onset disorder in individuals aged 17-57, and was not restricted to certain ethnic groups. All mutations occured in evolutionary conserved sites, and encoded amino acid substitutions at the amino- and carboxy-terminal ends of TRPC6. Two mutants, R895C and E897K, displayed increased current amplitudes, suggesting a pathogenic role of increased channel activity in TRPC6-related FSGS. In an effort to understand the molecular basis for TRPC6 in the kidney, the association of TRPC6 with the glomerular filter was studied. TRPC6 was found to be expressed in podocytes near the glomerular slit diaphragm. TRPC6 colocalized and associated with the slit diaphragm proteins nephrin and podocin. The presence of TRPC6 in podocyte foot processes and its association with slit diaphragm proteins supports a role of TRPC6 in the regulation of glomerular filtration. Since most proteinuric kidney diseases appear not as genetic but acquired disorders, TRPC6 was studied in humans with acquired glomerular diseases and in experimental models thereof. TRPC6 expression was induced in patients with minimal change disease and membranous glomerulopathy, as well as in passive Heymann nephritis (PHN) rats and puromycin aminonucleoside (PAN) rats. PAN-mediated podocyte injury correlated with increased receptor-operated calcium entry in vitro. TRPC6 gene delivery in mice was sufficient to induce proteinuria, and studies in cultured podocytes suggest that TRPC6 overexpression disrupts the actin cytoskeleton. The present data suggest that in both genetic and acquired forms of proteinuric kidney disease, misregulation of TRPC6 – either by presence of mutated hyperactive channels, or by precence of too many wildtype channels – plays a pathogenic role. Together, the results of this work may have broad implications for the pathophysiology of TRPC6-related human kidney diseases, and promote the development of anti-proteinuric drugs interfering with TRPC6 channel function.