A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease
A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease
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DOI：
10.1152/ajprenal.00551.2015
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发表时间：
2016-04-15
影响因子：
4.2
通讯作者：
Weimbs, Thomas
中科院分区：
文献类型：
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作者：
Kipp, Kevin R.;Rezaei, Mina;Weimbs, Thomas
常染色体显性多囊肾病 (ADPKD) 是终末期肾病的常见原因，美国尚无批准的治疗方法可以减缓疾病进展。哺乳动物雷帕霉素靶点 (mTOR) 信号通路在肾囊肿中异常激活，虽然 mTOR 抑制剂在啮齿动物模型中非常有效，但由于剂量限制性肾外副作用，ADPKD 的临床试验令人失望。由于已知 mTOR 受到营养物质和细胞能量状态的调节，我们假设饮食限制可能会影响肾囊肿的生长。在这里，我们发现，在具有马赛克条件性敲除 PKD1 的 ADPKD 直系同源小鼠模型中，食物摄入量 (RFI) 减少 23% 对多囊肾有深远影响。这种轻微的 RFI 水平不会影响正常的体重增加、导致营养不良或产生任何其他明显的副作用。 RFI 显着减缓了疾病进展：对照组的相对肾脏重量增加了 41%，对照组为 151%，囊肿衬里细胞的增殖率为 7.7%，对照组为 15.9%。采用 RFI 饮食的小鼠维持了肾功能，并且没有进展为终末期肾病。 mTORC1 信号传导的两个主要分支 S6 和 4EBP1 在囊肿衬里细胞中均被 RFI 抑制，这表明这种饮食方案可能比用雷帕拉类似物进行药理 mTOR 抑制更有效，后者主要影响 S6 分支。这些结果表明，多囊肾对营养供应或能量状态的轻微减少非常敏感。这项研究表明，轻微减少食物摄入量是延缓 ADPKD 患者疾病进展的潜在治疗干预措施。
Autosomal-dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease, and no approved treatment is available in the United States to slow disease progression. The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in renal cysts, and while mTOR inhibitors are highly effective in rodent models, clinical trials in ADPKD have been disappointing due to dose-limiting extrarenal side effects. Since mTOR is known to be regulated by nutrients and cellular energy status, we hypothesized that dietary restriction may affect renal cyst growth. Here, we show that reduced food intake (RFI) by 23% profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal body weight gain, cause malnutrition, or have any other apparent side effects. RFI substantially slows disease progression: relative kidney weight increase was 41 vs. 151% in controls, and proliferation of cyst-lining cells was 7.7 vs. 15.9% in controls. Mice on an RFI diet maintained kidney function and did not progress to end-stage renal disease. The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in cyst-lining cells by RFI, suggesting that this dietary regimen may be more broadly effective than pharmacological mTOR inhibition with rapalogs, which primarily affects the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to minor reductions in nutrient supply or energy status. This study suggests that a mild decrease in food intake represents a potential therapeutic intervention to slow disease progression in ADPKD patients.