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Am J Physiol Renal Physiol (October 3, 2006). doi:10.1152/ajprenal.00278.2006
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Submitted on July 20, 2006
Accepted on September 25, 2006

A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy

Myung-Ja Lee1, Denis Feliers1, Meenalakshmi M. Mariappan1, Kavithalakshmi Sataranatarajan1, Lenin Mahimainathan1, Nicolas Musi1, Marc Foretz2, Benoit Viollet3, Joel M Weinberg4, Goutam Ghosh Choudhury5, and Balakuntalam S Kasinath1*

1 Medicine, UTHSCSA, San Antonio, Texas, United States
2 Institut Cochin, Departement Endocrinologie Metabolisme et Cancer, Inserm U567, CNRS UMR 8104, Universite Paris 5, UM 3, Paris, France
3 Departement Endocrinologie Metabolisme et Cancer, Institut Cochin, Departement Endocrinologie Metabolisme et Cancer, Inserm U567, CNRS UMR 8104, Universite Paris 5, UM 3, Paris, France
4 Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, United States
5 University of Texas at San Antonio, United States; Medicine, UTHSCSA, San Antonio, Texas, United States; University of Texas at San Antonio

* To whom correspondence should be addressed. E-mail: kasinath{at}uthscsa.edu.

We tested the hypothesis that AMP-activated protein kinase (AMPK), an energy sensor, regulates diabetes-induced renal hypertrophy. In kidney glomerular epithelial cells (GEC), high glucose (30 mM), but not equimolar mannitol, stimulated de novo protein synthesis and induced hypertrophy in association with increase in phosphorylation of eukaryotic initiation factor 4E binding protein 1(4E-BP1) and decreased phosphorylation of eukaryotic elongation factor 2 (eEF2), regulatory events in mRNA translation. These high glucose-induced changes in protein synthesis were PI 3 kinase-, Akt- and mammalian target of rapamycin (mTOR) dependent and TGF{beta}-independent. High glucose reduced AMPK{alpha} subunit theronine (Thr) 172 phosphorylation that required Akt activation. Changes in AMP and ATP content could not fully account for high glucose-induced reduction in AMPK phosphorylation. Metformin and 5-aminiomidazole-4-carboxamide-1{beta}-riboside (AICAR) increased AMPK phosphorylation and inhibited high glucose stimulation of protein synthesis, and prevented high glucose-induced changes in phosphorylation of 4E-BP1 and eEF2. Expression of kinase-inactive AMPK further increased high glucose-induced protein synthesis. Renal hypertrophy in rats with type 1 diabetes was associated with reduction in AMPK phosphorylation and increase in mTOR activity. In diabetic rats, metformin and AICAR increased renal AMPK phosphorylation, reversed mTOR activation and inhibited renal hypertrophy, without affecting hyperglycemia. AMPK is a newly identified regulator of renal hypertrophy in diabetes.




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