Inactivation of Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse
Abstract
Background
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. NPHP2 is one of the 25 NPHP genes identified to date. In mouse, global knockout of Nphp2 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.
Methods
Here, we generated cell-type specific knockout mouse models of Nphp2 and characterized kidney morphology and phenotype. We additionally investigated the impact of removing cilia via deletion of the cilia biogenesis gene Ift88 on phenotype severity in Nphp2 mutants.
Results
Epithelial specific knockout of Nphp2 in Nphp2flox/flox; Ksp-Cre mutant mice resulted in renal cyst formation and severe fibrosis, while Nphp2flox/flox; Foxd1-Cre mice, where Nphp2 is deleted in stromal cells, displayed no observable phenotypes. Further, myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Nphp2flox/flox; Ksp-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Nphp2flox/flox; Ksp-Cre mutant kidney, supporting a significant role of cilia in Nphp2 function in vivo.
Conclusions
Our results highlight the critical role of renal epithelial cilia and epithelial-stromal communication in NPHP.
Significance statement
Nephronophthisis (NPHP) is a ciliopathy characterized by interstitial fibrosis and epithelial cysts in the kidney. A significant portion of end stage renal disease occurring before age 30 results from NPHP. However, the molecular etiology of NPHP remains to be elucidated. By generating and analyzing tissue specific knockout mouse models of Nphp2/Inversin, authors pinpoint defective epithelial cells as the driver for both epithelial cysts and interstitial fibrosis. Moreover, the profibrotic response is triggered before cyst formation in the epithelial-specific Nphp2 knockout model. Mechanistically, authors provide evidence that Nphp2 may function to inhibit a cilia-dependent pro-fibrotic and pro-cystic pathway.
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