Developmental switch dichotomizes kidney response to NPHP3 inactivation and treatment outcome

Abstract

Nephronophthisis (NPH) is n rare recessive kidney disease caused by biallelic variants in more than 25 NPHP genes encoding proteins that localize to primary cilia. It is characterized by three different forms depending on the age of onset and kidney lesions: infantile (cystic), juvenile/late onset (fibrotic). To date, the pathways linking altered primary cilia function to progressive kidney scarring in NPH remain poorly defined and therapeutic options are lacking. To address these questions, we generated two new mouse NPH models by inactivating Nphp3 specifically in kidney tubules either during embryogenesis or in adult, recapitulating the infantile and juvenile forms of the disease, respectively. Embryonic inactivation produced a rapid and severe cystic phenotype with tubular dedifferentiation, progressive interstitial fibrosis, inflammation and kidney failure, while postnatal inactivation led to a slowly progressive tubulointerstitial nephropathy characterized by tubular atrophy, fibrosis and immune cell infiltration without cyst formation. Strikingly, cilia were preserved in the early stages of both models, indicating that ciliogenesis impairment is not a primary driver of NPH3 pathogenesis. Transcriptomic profiling of the juvenile model revealed that disease initiation is driven by mitochondrial dysfunction, innate immune activation and aberrant cell cycle progression, while epithelial-to-mesenchymal transition and Wnt/{beta}-catenin remodelling emerges only at later stages of disease progression. Therapeutic intervention with the PGE1 (alprostadil) failed to rescue the cystic/infantile model but significantly attenuated fibrosis, inflammation and interstitial fibrosis in the fibrotic/juvenile model. The ability to recapitulate both disease forms through temporal modulation of gene inactivation suggests that primary cilia serve distinct, stage-specific functions in kidney tubular homeostasis, with different cellular processes being selectively vulnerable depending on the causative gene or variant. Collectively, these findings uncover early pathogenic mechanisms that may constitute tractable therapeutic targets for the treatment of nephronophthisis.