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ADPKD tissues display abnormalities in the biogenesis of the centrosome, a defect that can cause genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via \u201ccentrosome clustering,\u201d a key mechanism by which cells circumvent apoptosis. Here, we demonstrate that inhibiting centrosome clustering can counteract the proliferation of renal cystic cells with high incidences of CA. Using ADPKD human cells and mouse models, we show that preventing centrosome clustering with 2 inhibitors, CCB02 and PJ34, blocks cyst initiation and growth in vitro and in vivo. Inhibiting centrosome clustering activates a p53-mediated surveillance mechanism leading to apoptosis, reduced cyst expansion, decreased interstitial fibrosis, and improved kidney function. Transcriptional analysis of kidneys from treated mice identified pro-inflammatory signaling pathways implicated in CA-mediated cystogenesis and fibrosis. Our results demonstrate that centrosome clustering is a cyst-selective target for the improvement of renal morphology and function in ADPKD.<\/jats:p>","DOI":"10.1172\/jci.insight.172047","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T14:00:38Z","timestamp":1708524038000},"source":"Crossref","is-referenced-by-count":9,"title":["Inhibiting centrosome clustering reduces cystogenesis and improves kidney function in autosomal dominant polycystic kidney disease"],"prefix":"10.1172","volume":"9","author":[{"given":"Tao","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Medicine, Nephrology Division, Washington University School of Medicine, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aruljothi","family":"Mariappan","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf, D\u00fcsseldorf, 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