Mutations in PKD1 result in autosomal dominant polycystic kidney disease, which is characterized by increased proliferation of tubule cells leading to cyst initiation and subsequent expansion. Given the cell proliferation associated with cyst growth, an attractive therapeutic strategy has been to target the hyperproliferative nature of the disease. We previously demonstrated that the small molecule triptolide induces cellular calcium release through a polycystin-2-dependent pathway, arrests Pkd1-/- cell growth, and reduces cystic burden in Pkd1-/- embryonic mice. To assess cyst progression in neonates, we used the kidney-specific Pkd1flox/-;Ksp- Cre mouse model of autosomal dominant polycystic kidney disease, in which the burden of cysts is negligible at birth but then progresses rapidly over days. The number, size, and proliferation rate of cysts were examined. Treatment with triptolide significantly improved renal function at postnatal day 8 by inhibition of the early phases of cyst growth. Because the proliferative index of kidney epithelium in neonates versus adults is significantly different, future studies will need to address whether triptolide delays or reduces cyst progression in the Pkd1 adult model.
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