Spatiotemporal dynamics of renal distal convoluted tubule dilatation and cyst formation in nephronophthisis type 1 mice.

Nephronophthisis (NPH), a rare but serious ciliopathy, is the predominant genetic cause of end-stage kidney disease (ESKD) in children and adolescents. Renal tubular dilatation and cyst formation are key pathological features of NPH. The mechanisms underlying renal cystogenesis remain poorly understood. This study employed sex-balanced Nphp1 deletion gene knockout (Nphp1^KO) mice at 8, 12, and 24 weeks of age to investigate the spatiotemporal dynamics of renal tubules and cyst development, aiming to identify the origins of renal cysts. Quantitative evaluation of cyst progression revealed a significant increase in cyst number from 8 to 12 weeks of age, but no substantial change from 12 to 24 weeks. Additionally, cyst size remained stable throughout the study period. Serial section tracing and segment-specific tubular marker analysis confirmed that these cysts originated from the distal convoluted tubule (DCT), which displayed segmental dilation while preserving anatomical connections with adjacent, morphologically normal DCT. 3D reconstruction revealed that renal cysts appeared either as a single or in a bead-like arrangement. We demonstrated that human renal cyst epithelial cells from patients with NPH1 also originate primarily from the DCT. This study provides critical experimental evidence of the histopathological features of renal cysts in NPH1, advancing our understanding of the pathogenesis of NPHP-associated tubular dilation and cystogenesis.