Inhibition of Centrosome Clustering Reduces Cystogenesis and Improves Kidney Function in Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited monogenic disorder accounting for ~5% of patients with renal failure. Yet, therapeutics for the treatment of ADPKD remain limited. ADPKD tissues display defects in the biogenesis of the centrosome which causes genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors that drive cyst growth and fibrosis. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which often causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via centrosome clustering, 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 blocking centrosome clustering with two inhibitors, CCB02 and PJ34, blocks cyst initiation and growth in vitro and in vivo. Inhibition of centrosome clustering activates a p53-mediated mitotic surveillance mechanism leading to apoptosis, reduced cyst expansion, 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 provide the first evidence that centrosome clustering is a cyst-selective target for the improvement of renal morphology and function in ADPKD.

Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution

“…The kidneys for Pkd1 fl/fl ; Six2 Cre mouse model were analyzed at P7. The Pkd1 p.R3269C knock-in mice (equivalent to human Pkd1 p.R3277C mutation [ Pkd1 RC/RC ])(40, 44) were analyzed at 11 months of age.…”