{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T22:52:42Z","timestamp":1781131962640,"version":"3.54.1"},"reference-count":31,"publisher":"American Society for Clinical Investigation","issue":"12","license":[{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"vor","delay-in-days":32,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["R01DK131047"],"award-info":[{"award-number":["R01DK131047"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U24DK126110"],"award-info":[{"award-number":["U24DK126110"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,24]]},"abstract":"\n Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the\n PKD1<\/jats:italic>\n or\n PKD2<\/jats:italic>\n gene, show signs of complement activation in the urine and cystic fluid, but their pathogenic role in cystogenesis is unclear. We tested the causal relationship between complement activation and cyst growth using a Pkd1\n KO<\/jats:sup>\n renal tubular cell line and newly generated conditional\n \n Pkd1\n \u2013\/\u2013<\/jats:sup>\n <\/jats:italic>\n \n C3\n \u2013\/\u2013<\/jats:sup>\n <\/jats:italic>\n mice.\n Pkd1<\/jats:italic>\n -deficient tubular cells have increased expression of complement-related genes (\n C3<\/jats:italic>\n ,\n C5<\/jats:italic>\n ,\n CfB<\/jats:italic>\n ,\n C3ar<\/jats:italic>\n , and\n C5ar1<\/jats:italic>\n ), while the gene and protein expression of complement regulators DAF, CD59, and Crry is decreased.\n \n Pkd1\n \u2013\/\u2013<\/jats:sup>\n <\/jats:italic>\n \n C3\n \u2013\/\u2013<\/jats:sup>\n <\/jats:italic>\n mice are unable to fully activate the complement cascade and are characterized by a significantly slower kidney cystogenesis, preserved renal function, and reduced intrarenal inflammation compared with\n \n Pkd1\n \u2013\/\u2013<\/jats:sup>\n <\/jats:italic>\n \n C3\n +\/+<\/jats:sup>\n <\/jats:italic>\n controls. Transgenic expression of the cytoplasmic C-terminal tail of\n Pkd1<\/jats:italic>\n in Pkd1\n KO<\/jats:sup>\n cells lowered\n C5ar1<\/jats:italic>\n expression, restored\n Daf<\/jats:italic>\n levels, and reduced cell proliferation. Consistently, both DAF overexpression and pharmacological inhibition of C5aR1 (but not C3aR) reduced Pkd1\n KO<\/jats:sup>\n cell proliferation. In conclusion, the loss of\n Pkd1<\/jats:italic>\n promotes unleashed activation of locally produced complement by downregulating DAF expression in renal tubular cells. Increased C5a formation and C5aR1 activation in tubular cells promotes cyst growth, offering a new therapeutic target.\n <\/jats:p>","DOI":"10.1172\/jci.insight.175220","type":"journal-article","created":{"date-parts":[[2024,6,23]],"date-time":"2024-06-23T14:00:36Z","timestamp":1719151236000},"source":"Crossref","is-referenced-by-count":5,"title":["Reduced decay-accelerating factor expression promotes complement-mediated cystogenesis in murine ADPKD"],"prefix":"10.1172","volume":"9","author":[{"given":"Sofia","family":"Bin","sequence":"first","affiliation":[{"name":"Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."},{"name":"Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero- University of Bologna, Italy."},{"name":"Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miran","family":"Yoo","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-5656","authenticated-orcid":true,"given":"Paolo","family":"Molinari","sequence":"additional","affiliation":[{"name":"Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Gentile","sequence":"additional","affiliation":[{"name":"Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."},{"name":"Unit\u00e0 Operativa Nefrologia, Azienda-Ospedaliero University of Parma, Department of Medicine and Syrgery, University of Parma, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9929-8518","authenticated-orcid":true,"given":"Kelly","family":"Budge","sequence":"additional","affiliation":[{"name":"Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cantarelli","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Nefrologia, Azienda-Ospedaliero University of Parma, Department of Medicine and Syrgery, University of Parma, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaseen","family":"Khan","sequence":"additional","affiliation":[{"name":"Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-8551","authenticated-orcid":true,"given":"Gaetano","family":"La Manna","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero- University of Bologna, Italy."},{"name":"Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Dvorina","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7837-0923","authenticated-orcid":true,"given":"Paolo","family":"Cravedi","sequence":"additional","affiliation":[{"name":"Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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