Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse

作者：Yuanyuan Li, Wenyan Xu, Svetlana Makova, Martina Brueckner, Zhaoxia Sun · 发表于：eLife · 年份：2023 · DOI：10.7554/elife.82395 · 被引用次数：10 · 研究领域：Genetic and Kidney Cyst Diseases、Renal and related cancers、Pediatric Urology and Nephrology Studies

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. INVS/NPHP2 is one of the over 25 NPHP genes identified to date. In mouse, global knockout of Invs 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 Invs , investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial-specific knockout of Invs in Invs flox/flox ;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invs flox/flox ;Foxd1-Cre mice, where Invs 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 Invs flox/flox ;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invs flox/flox ;Cdh16-Cre mutant kidney, supporting a significant inter...