p21(WAF1/CIP1) Expression is Differentially Regulated by Metformin and Rapamycin.

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.