Leuenroth Stephanie J, Bencivenga Natasha, Igarashi Peter, Somlo Stefan, Crews Craig M
Yale University, Department MCD Biology, P.O. Box 208103, New Haven, CT 06520-8103, USA.
J Am Soc Nephrol. 2008 Sep;19(9):1659-62. doi: 10.1681/ASN.2008030259. Epub 2008 Jul 23.
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 Pkd1(flox/-);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.
多囊蛋白-1（PKD1）的突变会导致常染色体显性遗传性多囊肾病，其特征是肾小管细胞增殖增加，从而引发囊肿并随后扩大。鉴于囊肿生长与细胞增殖相关，一种有吸引力的治疗策略是针对该疾病的过度增殖特性。我们之前证明，小分子雷公藤内酯醇通过多囊蛋白-2依赖的途径诱导细胞钙释放，抑制Pkd1基因敲除（Pkd1-/-）细胞的生长，并减轻Pkd1-/-胚胎小鼠的囊肿负担。为了评估新生小鼠的囊肿进展情况，我们使用了常染色体显性遗传性多囊肾病的肾脏特异性Pkd1（flox/-）；Ksp-Cre小鼠模型，在该模型中，出生时囊肿负担可忽略不计，但随后几天会迅速进展。我们检查了囊肿的数量、大小和增殖率。雷公藤内酯醇治疗通过抑制囊肿生长的早期阶段，在出生后第8天显著改善了肾功能。由于新生小鼠与成年小鼠肾脏上皮细胞的增殖指数存在显著差异，未来的研究需要探讨雷公藤内酯醇是否会延缓或减轻Pkd1成年模型中的囊肿进展。
