{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:41:04Z","timestamp":1793932864163,"version":"4.8.0"},"reference-count":47,"publisher":"American Physiological Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2015,6,1]]},"abstract":"<jats:p>Nephrotic syndrome is a disease of glomerular permselectivity that can arise as a consequence of heritable or acquired changes to the integrity of the glomerular filtration barrier. We recently reported two siblings with heritable nephrotic syndrome caused by a loss of function mutation in the gene ARHGDIA, which encodes for Rho guanine nucleotide dissociation inhibitor-\u03b1 (GDI\u03b1). GDIs are known to negatively regulate Rho-GTPase signaling. We hypothesized that loss of GDI\u03b1 sensitizes podocytes to external injury via hyperactivation of Rho-GTPases and p38 MAPK. We examined the response of cultured podocytes with and without knockdown of GDI\u03b1 to LPS injury by assessing the levels of phospho-p38 as well as the degree of synaptopodin loss. GDI\u03b1 knockdown podocytes showed more pronounced and sustained p38 phosphorylation in response to LPS compared with control podocytes, and this was blunted significantly by the Rac1 inhibitor. In LPS-treated control podocytes, synaptopodin degradation occurred, and this was dependent on p38, the proteasome, and cathepsin L. In GDI\u03b1 knockdown podocytes, the same events were triggered, but the levels of synaptopodin after LPS treatment were significantly lower than in control podocytes. These experiments reveal a common pathway by which heritable and environmental risk factors converge to injure podocytes, from Rac1 hyperactivation to p38 phosphorylation and synaptopodin degradation via the ubiquitin-proteasome pathway and cathepsin L.<\/jats:p>","DOI":"10.1152\/ajprenal.00225.2014","type":"journal-article","created":{"date-parts":[[2014,12,11]],"date-time":"2014-12-11T03:36:45Z","timestamp":1418269005000},"page":"F1207-F1216","source":"Crossref","is-referenced-by-count":8,"title":["Loss of Rho-GDI\u03b1 sensitizes podocytes to lipopolysaccharide-mediated injury"],"prefix":"10.1152","volume":"308","author":[{"given":"Richard","family":"Robins","sequence":"first","affiliation":[{"name":"Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University Health Centre, 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