{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:56:47Z","timestamp":1793692607674,"version":"4.5.1"},"reference-count":72,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000291","name":"Kidney Research UK","doi-asserted-by":"crossref","award":["ST3\/2011"],"award-info":[{"award-number":["ST3\/2011"]}],"id":[{"id":"10.13039\/501100000291","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,20]]},"abstract":"<jats:p>\n                    Mutations in\n                    <jats:italic>PKD1<\/jats:italic>\n                    (encoding for polycystin-1 [PC1]) are found in 80%\u201385% of patients with autosomal dominant polycystic kidney disease (ADPKD). We tested the hypothesis that changes in actin dynamics result from\n                    <jats:italic>PKD1<\/jats:italic>\n                    mutations through dysregulation of compartmentalized centrosomal RhoA signaling mediated by specific RhoGAP (ARHGAP) proteins resulting in the complex cellular cystic phenotype. Initial studies revealed that the actin cytoskeleton was highly disorganized in cystic cells derived from patients with\n                    <jats:italic>PKD1<\/jats:italic>\n                    and was associated with an increase in total and centrosomal active RhoA and ROCK signaling. Using cilia length as a phenotypic readout for centrosomal RhoA activity, we identified ARHGAP5, -29, and -35 as essential regulators of ciliation in normal human renal tubular cells. Importantly, a specific decrease in centrosomal ARHGAP35 was observed in\n                    <jats:italic>PKD1<\/jats:italic>\n                    -null cells using a centrosome-targeted proximity ligation assay and by dual immunofluorescence labeling. Finally, the ROCK inhibitor hydroxyfasudil reduced cyst expansion in both human\n                    <jats:italic>PKD1<\/jats:italic>\n                    3D cyst assays and an inducible\n                    <jats:italic>Pkd1<\/jats:italic>\n                    mouse model. In summary, we report a potentially novel interaction between PC1 and ARHGAP35 in the regulation of centrosomal RhoA activation and ROCK signaling. Targeting the RhoA\/ROCK pathway inhibited cyst formation in vitro and in vivo, indicating its relevance to ADPKD pathogenesis and for developing new therapies to inhibit cyst initiation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.135385","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T12:02:56Z","timestamp":1594728176000},"source":"Crossref","is-referenced-by-count":42,"title":["Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling"],"prefix":"10.1172","volume":"5","author":[{"given":"Andrew J.","family":"Streets","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4487-9531","authenticated-orcid":true,"given":"Philipp 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