Inactivation of / in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.

Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently, no targeted therapy is available for this disease. is one of the over 25 NPHP genes identified to date. In mouse, global knockout of leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type-specific knockout mouse models of , investigated the impact of removing cilia genetically on phenotype severity in mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on mutants. Epithelial-specific knockout of in mutant mice resulted in renal cyst formation and severe stromal fibrosis, while mice, where is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the mutant kidney, supporting a significant interaction of cilia and function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.