Transforming Hyperglycemia into Hypertrophy

Science Signaling  28 Jul 2009:
Vol. 2, Issue 81, pp. ec256
DOI: 10.1126/scisignal.281ec256

Chronic exposure to high concentrations of glucose leads to increased protein synthesis and cellular hypertrophy, a process that can have deleterious consequences in conditions such as diabetes (see Goraksha-Hicks and Rathmell). Transforming growth factor–β (TGF-β) stimulates cellular hypertrophy by means of the phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR (mammalian target of rapamycin) signaling pathway and, noting various data suggesting a link between increased glucose and TGF-β signaling, Wu and Derynk explored the possibility that glucose-dependent hypertrophy might involve TGF-β signaling through this pathway. After determining that 24 hours' exposure to 25 mM glucose elicited an increase in the size and protein content of various types of cultured cells, including mouse embryo fibroblasts (MEFs) and rat kidney epithelial NRK-52E cells, the authors showed that the effects of glucose on cell size and protein content were lost in MEFs lacking type 1 TGF-β receptors (TβRI) and in cells in which the kinase activity of TβRI was inhibited with SB43152. Glucose stimulated the phosphorylation, nuclear translocation, and transcriptional activity of the TGF-β effector Smad3 in the absence of added TGF-β and enhanced TGF-β−mediated transcription of a Smad3-responsive reporter. Moreover, glucose elicited SB43152-dependent Akt phosphorylation, and its effects on cell size were blocked by the mTOR inhibitor rapamycin. Glucose stimulated an increase in the plasma membrane localization of TβRI and TβRII without affecting their cellular abundance per se. It also increased the amount of active TGF-β in conditioned medium, an effect that depended on activation of latent TGF-β, rather than de novo protein synthesis. Pharmacological analysis indicated that glucose-dependent activation of TGF-β depended on matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Moreover, knockdown of MMP-2 or MMP-9 with siRNA decreased not only the glucose-dependent TGF-β activation but also the glucose-dependent increase in cell size. Thus, the authors conclude that TGF-β signaling is critical to glucose-induced cellular hypertrophy.

L. Wu, R. Derynck, Essential role of TGF-β signaling in glucose-induced cell hypertrophy. Dev. Cell. 17, 35–48 (2009).[PubMed]

P. Goraksha-Hicks, J. C. Rathmell, TGF-β: A new role for an old AktTOR. Dev. Cell. 17, 6–8 (2009).[PubMed]