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International Journal of Chronic Diseases
Volume 2014, Article ID 327640, 17 pages
Research Article

p21WAF1/CIP1 Expression is Differentially Regulated by Metformin and Rapamycin

Renal Unit and Diabetes Clinical Research Unit, Derriford Hospital, Plymouth, PL6 8DH, UK

Received 4 December 2013; Revised 3 February 2014; Accepted 13 February 2014; Published 25 March 2014

Academic Editor: Benjamin Kefas

Copyright © 2014 Zoltan Molnar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.