NPHP2 in ciliary function, renal fibrosis and cyst formation

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This proposal focuses on both cell autonomous and non-autonomous function of the nephronophthisis (NPHP) gene, Nphp2, in renal fibrosis and cyst formation. NPHP is a recessive renal ciliopathy characterize by interstitial fibrosis and cysts. Although NPHP accounts for a significant portion of end stage renal disease in children and young adults, currently no targeted therapy is available for this disease and the underlying molecular etiology, particular for interstitial fibrosis, is not well understood, even though NPHP proteins have been put into different modules biochemically. The lack of knowledge hampers the effort to develop targeted therapy for this disease. Previous work showed that mouse whole-body knockout model of Nphp2 displays renal fibrosis and cysts at the neonatal stage. By generating and analyzing epithelial and complementary stromal specific knockout mouse models of Nphp2, we pinpointed defective epithelial cells as the driver for both interstitial fibrosis and epithelial cyst formation. In addition, myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the epithelial specific Nphp2 mutants. Moreover, abrogation of cilia genetically partially suppresses the phenotype of Nphp2 mutants, suggesting that cilia play a significant role in Nphp2 function. The central hypothesis of this project is that Nphp2 inhibits a cilia-dependent profibrotic and pro-cystic pathway in renal epithelial cells and that both cell autonomous and non-autonomous responses contribute to disease progression. Two specific aims were proposed to test this hypothesis. Aim 1 focuses on renal epithelial cells. A combination of approaches, from in vivo phenotype characterization, transcriptome profiling to pathway analysis to identify key pathways that are disrupted in Nphp2 mutant epithelial cells. Aim 2 focuses on epithelial-interstitial crosstalk and will determine how stromal cells respond to epithelial cells with defective NPHP2 and whether stromal cells modify phenotypes of Nphp2 mutants. Completion of this project will provide critical insight into the molecular and cellular etiology of NPHP and cilia-mediated signaling under diverse physiological and disease states.