Department of Pediatrics, University Children’s Hospital, Rostock, Rostock, Germany.
Nephrol Dial Transplant. 2011 Jan;26(1):92-100. doi: 10.1093/ndt/gfq384. Epub 2010 Jul 7.
Activation of the mTOR pathway has been implicated in the mediation of the progression of polycystic kidney disease (PKD). Whereas targeted inhibition of mTOR has been proven to be effective in various animal models of autosomal dominant PKD, its efficacy in autosomal recessive PKD (ARPKD) remains to be elucidated. We examined the effects of sirolimus in PCK rats, an orthologous animal model of human ARPKD.
Weaned PCK rats (n = 85) and SD-control rats (n = 72) received drinking water without and with sirolimus (corresponding to a daily intake of 2 mg/kg body weight) for 4, 8 and 12 weeks, respectively. The renal and hepatic functions were monitored throughout the treatment periods. Kidneys and livers were harvested and investigated with respect to progression of fibrosis, and number and size of cysts using the QWin image analysis programme. Expression of Akt, mTOR and its downstream target pS6K were assessed by immunohistochemistry.
Five out of 43 sirolimus-treated PCK rats, but none of the controls, died during the study. Sirolimus treatment resulted in slightly reduced weight gain. In PCK rats, grossly enlarged kidney and livers as well as hepatic fibrosis together with enlarged bile ducts were readily detectable. Whereas activation of Akt/mTOR signalling was hardly detectable in the kidneys of SD rats, strong signals were seen in the kidneys of PCK rats. Despite a significantly reduced relative kidney weight after 12 weeks of treatment (P < 0.05), neither fibrosis and cyst area nor renal function improved during treatment. Sirolimus-treated PCK rats showed only a minor inhibition of renal mTOR-specific phosphorylation of S6K. Male PCK rats on sirolimus presented with increased concentrations of bile acids and bilirubin compared with controls (each P < 0.05 at 12 weeks). Similar, albeit non-significant, effects were noted in female PCK rats.
Sirolimus failed to attenuate progression of kidney and liver disease in PCK rats. The lack of a protective effect might be due to intrinsic or acquired rapamycin resistance in this animal model of ARPKD.
mTOR 途径的激活被认为与多囊肾病 (PKD) 的进展有关。虽然靶向抑制 mTOR 已被证明在各种常染色体显性 PKD 的动物模型中有效，但它在常染色体隐性 PKD (ARPKD) 中的疗效仍有待阐明。我们研究了雷帕霉素在 PCK 大鼠中的作用，PCK 大鼠是人类 ARPKD 的同源动物模型。
断奶后的 PCK 大鼠 (n = 85) 和 SD 对照大鼠 (n = 72) 分别饮用不含和含雷帕霉素的水 (相当于每天摄入 2mg/kg 体重)，持续 4、8 和 12 周。在整个治疗期间监测肾脏和肝脏功能。用 QWin 图像分析程序检测纤维化进展、囊肿数量和大小，收获肾脏和肝脏进行研究。通过免疫组织化学评估 Akt、mTOR 及其下游靶标 pS6K 的表达。
在研究期间，43 只雷帕霉素治疗的 PCK 大鼠中有 5 只死亡，但对照组无一例死亡。雷帕霉素治疗导致体重略有增加。PCK 大鼠的肾脏和肝脏明显增大，肝纤维化和胆管扩张也很容易检测到。尽管在 SD 大鼠肾脏中几乎检测不到 Akt/mTOR 信号的激活，但在 PCK 大鼠肾脏中却能检测到强烈的信号。尽管在治疗 12 周后相对肾脏重量显著降低 (P < 0.05)，但纤维化和囊肿面积或肾功能在治疗过程中均未改善。雷帕霉素治疗的 PCK 大鼠肾脏 mTOR 特异性 S6K 磷酸化仅受到轻微抑制。与对照组相比，雷帕霉素治疗的雄性 PCK 大鼠的胆汁酸和胆红素浓度升高 (均在 12 周时 P < 0.05)。雌性 PCK 大鼠也出现了类似的、但无统计学意义的影响。
雷帕霉素未能减轻 PCK 大鼠的肾脏和肝脏疾病进展。缺乏保护作用可能是由于该 ARPKD 动物模型中存在内在或获得性雷帕霉素耐药性。
