Kipp Kevin R, Rezaei Mina, Lin Louis, Dewey Elyse C, Weimbs Thomas
Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California.
Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, California
Am J Physiol Renal Physiol. 2016 Apr 15;310(8):F726-F731. doi: 10.1152/ajprenal.00551.2015. Epub 2016 Jan 13.
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.
常染色体显性多囊肾病（ADPKD）是终末期肾病的常见病因，在美国尚无获批用于减缓疾病进展的治疗方法。雷帕霉素的哺乳动物靶点（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ADPKD的临床试验却因剂量限制性肾外副作用而令人失望。由于已知mTOR受营养物质和细胞能量状态的调节，我们推测饮食限制可能会影响肾囊肿的生长。在此，我们表明，在一个PKD1镶嵌条件性敲除的ADPKD直系同源小鼠模型中，食物摄入量减少23%（RFI）会对多囊肾产生深远影响。这种轻度的RFI水平不会影响正常体重增加，不会导致营养不良，也没有任何其他明显的副作用。RFI显著减缓疾病进展：对照组相对肾重量增加41%，而RFI组为151%；对照组囊肿衬里细胞增殖为15.9%，而RFI组为7.7%。接受RFI饮食的小鼠维持了肾功能，未进展至终末期肾病。mTORC1信号的两个主要分支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使用雷帕霉素类似物进行的药理学mTOR抑制更具广泛疗效，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降低极为敏感。这项研究表明，轻度减少食物摄入量代表了一种减缓ADPKD患者疾病进展的潜在治疗干预措施。
