Defined Dietary Intervention Overrides Injury-Accelerated Cystogenesis in a Mouse Model of ADPKD

Background: Mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD), yet the mechanisms driving cystogenesis remain incompletely understood. Renal injury is known to accelerate cyst formation, while dietary restriction has shown promise in slowing disease progression in preclinical models. Here, we investigate the combined effects of acute kidney injury and a defined dietary intervention on cyst development in a mouse model of ADPKD. Methods: Tamoxifen-inducible Pkd2 conditional knockout mice (CaggCreER; Pkd2fl/fl) were either left uninjured or subjected to single- (1X 9 mg/kg) or repeated-dose cisplatin (4X 5 mg/kg) to induce acute and chronic renal injury. To assess the impact of dietary intervention on cystogenesis, a defined dietary regimen (consisting of a fixed daily ration of 3.6 g of chow administered at 4 PM) was implemented on mice after tamoxifen induction at 8 weeks of age. Cyst burden, tubular injury, epithelial proliferation, and macrophage infiltration were evaluated. Results: The defined dietary regimen effectively suppressed cyst formation and slowed cyst progression in non-injured Pkd2-mutant mice, with the extent of protection dependent on the timing of dietary initiation. In renal injury models, cisplatin treatment markedly accelerated cyst development compared to PBS-treated controls, with cysts predominantly localized to injured tubules. However, implementing the dietary intervention significantly attenuated cyst burden in both acutely and chronic injured mice, restoring cyst severity to levels comparable to non-injured mutants. Notably, this protective effect occurred despite the continued presence of tubular injury, as evidenced by sustained Kim1 and Sox9 expression. Furthermore, diet-restricted kidneys displayed reduced epithelial cell proliferation and diminished macrophage infiltration within cystic regions. Conclusion: Our findings highlight that both acute and chronic renal injury promotes cyst formation in ADPKD, but this process can be markedly attenuated by dietary intervention. These results suggest that nutritional modulation may represent a viable strategy to counteract injury-driven cyst progression in ADPKD. Funding: NIDDK Support, Private Foundation Support