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 p21WAF1/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. 1. Introduction There has been a dramatic increase in the prevalence of diabetes mellitus in recent years [1]. The chronic effects of diabetes may manifest in macro- and microvascular complications that are the major causes of morbidity and mortality in patients with diabetes. Diabetic nephropathy (DN), one of the microvascular complications, is a leading cause of death from kidney failure [2, 3]. Apart from haemodynamic factors, hyperglycaemia has been shown to be an underlying cause of pathogenesis in DN. The damaging effects of hyperglycaemia have been partly attributed to increased cellular glucose uptake in cells that are not protected from high ambient glucose levels. Early cellular changes in the development of DN include hyperplasia and hypertrophy [4]. Several investigators have associated the expression of Cip/Kip cyclin-dependent kinase (CDK) inhibitors, p21 and p27, with glomerular hypertrophy [5–7]. It has been proposed that p21 and p27 may be involved in hypertrophy independently of their cell cycle regulatory properties (Monkawa 2002). Furthermore, the induction of p21 and p27 is also required for senescent arrest, a molecular signature of hypertrophic changes in the early stages of the development of diabetic kidney disease [8]. The fact that p21 null mice do not develop glomerular hypertrophy supports the importance of p21 in DN [9]. The activation of the mammalian target of rapamycin (mTOR), a serine/threonine kinase, plays a pivotal role in the pathologic forms of hypertrophy in the kidneys
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