Molnar Zoltan, Millward Ann B, Tse Wai, Demaine Andrew G
Renal Unit and Diabetes Clinical Research Unit, Derriford Hospital, Plymouth, PL6 8DH, UK.
Int J Chronic Dis. 2014;2014:327640. doi: 10.1155/2014/327640. Epub 2014 Mar 25.
The mammalian target of rapamycin (mTOR) pathway plays an important role in the development of diabetic nephropathy and other age-related diseases. One of the features of DN is the elevated expression of p21(WAF1/CIP1). However, the importance of the mTOR signalling pathway in p21 regulation is poorly understood. Here we investigated the effect of metformin and rapamycin on mTOR-related phenotypes in cell lines of epithelial origin. This study reports that metformin inhibits high glucose-induced p21 expression. High glucose opposed metformin in regulating cell size, proliferation, and protein synthesis. These effects were associated with reduced AMPK activation, affecting downstream mTOR signalling. However, the inhibition of the mTOR pathway by rapamycin did not have a negative effect on p21 expression, suggesting that metformin regulates p21 upstream of mTOR. These findings provide support for the hypothesis that AMPK activation may regulate p21 expression, which may have implications for diabetic nephropathy and other age-related pathologies.
雷帕霉素靶蛋白（mTOR）通路在糖尿病肾病及其他与年龄相关疾病的发展中起重要作用。糖尿病肾病的特征之一是p21（WAF1/CIP1）表达升高。然而，mTOR信号通路在p21调控中的重要性却鲜为人知。在此，我们研究了二甲双胍和雷帕霉素对上皮来源细胞系中mTOR相关表型的影响。本研究报告称，二甲双胍可抑制高糖诱导的p21表达。高糖在调节细胞大小、增殖和蛋白质合成方面与二甲双胍作用相反。这些效应与AMPK激活减少有关，进而影响下游mTOR信号传导。然而，雷帕霉素对mTOR通路的抑制对p21表达并无负面影响，这表明二甲双胍在mTOR上游调节p21。这些发现为以下假说提供了支持，即AMPK激活可能调节p21表达，这可能对糖尿病肾病及其他与年龄相关的病理状况具有重要意义。
