Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling.

摘要: Abstract PodocyteTRPC6 channels have been implicated in glomerular diseases. Syndecan-4 (Sdc4) is a membrane proteoglycan that can be cleaved to release soluble ectodomain capable of paracrine and autocrine signaling. We confirmed overexpression Sdc4 core protein increases surface abundance TRPC6 cultured podocytes, whereas knockdown has the opposite effect. Exposure also increased TRPC6, cationic currents evoked by diacylglycerol analog podocytes. generation reactive oxygen species (ROS), reduced activation RhoA, Rac1, nuclear NFATc1, total β3-integrin. The effects on cell-surface were blocked ROS quencher TEMPOL, Rac1 inhibitor NSC-23766, but not inhibition calcineurin–NFATc1 co-immunoprecipitates with β3-integrin Moreover, generation, RhoA modulation, NFATc1 cilengitide, selective outside-in signaling through α v -containing integrins. TNF, or serum from three patients recurrent FSGS relapse, shedding podocyte ectodomains into surrounding medium. This was observed after treating podocytes metalloproteinase ADAM17 protein. Increased concentrations detected urine rats during acute puromycin aminonucleoside nephrosis. Locally generated may play role regulating channels, contribute pathology.