Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD
Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD
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DOI：
10.1093/ndt/gfp777
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发表时间：
2010-07-01
影响因子：
6.1
通讯作者：
Crews, Craig M.
中科院分区：
文献类型：
--
作者：
Leuenroth, Stephanie J.;Bencivenga, Natasha;Crews, Craig M.
方法。在这里，利用干扰素响应性 Mx1Cre 重组酶的 Pkd1-floxed 诱导小鼠模型来测试小分子雷公藤甲素的效果。相对于其他 Pkd1 失活模型，这种新生儿到成人过渡模型中的囊肿进展被减弱。在表征这些小鼠中诱导性囊肿形成的特征后，分析了雷公藤甲素或媒介物处理的动物的肾囊肿的发展。结果。尽管出生后第 P10 和 P12 天的 Pkd1 缺失导致到第 35 天出现大量囊肿，但从第 P16 天开始每天注射雷公藤甲素显着减少了每个肾脏的囊肿总数，对微囊的数量和总体囊肿负担有显着影响。此外，通过雷公藤甲素治疗的小鼠的血尿素氮水平评估的肾功能在 P22 和 P35 时间点也得到改善。由于 Pkd1(flox/flox);Mx1Cre 模型之前尚未用于药物开发研究，因此还测试了 6 个月的成人 Pkd1 失活研究的可行性。虽然肾囊肿的形成本质上是最小的和局灶性的，但这些 Pkd1 缺陷小鼠的肝脏严重囊肿、肿大且苍白。结论。这些结果表明 ADPKD 的 Pkd1(flox/flox);Mx1Cre 模型适合短期肾囊肿形成药物研究；然而，这对于长期治疗研究来说可能是个问题，因为广泛的肝囊肿和纤维化可能会损害药物代谢。
Methods. Here, a Pkd1-floxed inducible mouse model using the interferon responsive Mx1Cre-recombinase was utilized to test the effect of the small molecule triptolide. Relative to other Pkd1 inactivation models, cyst progression in this neonatal to adult transition model is attenuated. Following the characterization of inducible cyst formation in these mice, the development of kidney cysts from triptolide or vehicle-treated animals was analysed.Results. Although Pkd1 deletion on postnatal Days P10 and P12 resulted in numerous cysts by P35, daily injections with triptolide beginning on Day P16 significantly reduced the total number of cysts per kidney, with a pronounced effect on the number of microcysts and the overall cystic burden. Additionally, renal function as assessed by blood urea nitrogen levels was also improved in triptolide-treated mice at both the P22 and P35 time points. As the Pkd1(flox/flox);Mx1Cre model has not been previously used for drug development studies, the feasibility of a 6-month adult Pkd1 inactivation study was also tested. While kidney cyst formation was minimal and focal in nature, livers of these Pkd1-deficient mice were severely cystic, enlarged and pale.Conclusions. These results suggest that the Pkd1(flox/flox);Mx1Cre model of ADPKD is amenable to short-term kidney cyst formation drug studies; however, it may be problematic for long-term therapeutic research where widespread liver cysts and fibrosis could compromise drug metabolism.