Renal Tubule-Specific Deletion of Nephrocystin 3 (Nphp3) Causes Infantile Nephronophthisis-like Phenotypes in Mice.

Patients with nephronophthisis caused by nephrocystin 3 (NPHP3) variants rapidly progress to end-stage kidney disease. However, existing Nphp3 mouse models fail to fully recapitulate the characteristics of this disease. We generated a renal tubule-specific Nphp3 knockout mouse model that more accurately mirrors the human disease course. The mouse model was first validated by confirming the loss of Nphp3 protein expression in renal tubules. Comprehensive phenotypic analyses were then performed to assess both renal and extrarenal manifestations. The origin of renal cysts was investigated, and the underlying mechanisms were further validated. We successfully generated a renal tubule-specific Nphp3 knockout mouse model (Cdh16-Cre; Nphp3flox/flox). These mice exhibited a markedly shortened lifespan (5-8 weeks) and developed key features of infantile nephronophthisis, including early-onset renal cysts originating from distal tubules and collecting ducts, progressive interstitial fibrosis that was evident by postnatal week 2, a rapid decline in kidney function, and increased urinary protein levels. Importantly, treatment with the vasopressin V2 receptor antagonist tolvaptan or the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040) significantly attenuated cyst growth and improved kidney morphology, confirming shared pathogenic pathways with other Nphp3 models. We established a renal tubule-specific Nphp3 knockout mouse model that accurately recapitulates the aggressive infantile form of nephronophthisis characterized by early cystogenesis, progressive fibrosis, and a shortened lifespan, and is ideal for evaluating novel interventions against this currently untreatable ciliopathy.