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Akt activation and augmented fibronectin production in hyperhexosemia

¹Department of Pathology, University of Western Ontario, London, Ontario, Canada; and ²Vascular Biology Research Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

Submitted 1 May 2007 ; accepted in final form 24 July 2007

Dysmetabolic state in diabetes may lead to augmented synthesis of extracellular matrix (ECM) proteins. In the endothelial cells, we have previously demonstrated that glucose-induced fibronectin (FN) production and that of its splice variant, EDB⁺FN, is regulated by protein kinase B (PKB, also known as Akt). In this study, we investigated the role of Akt1 in ECM protein production in the organs affected by chronic diabetic complications. We studied Akt1/PKB knockout mice and wild-type control littermates. To avoid confounding effects of systemic insulin, we used 30% galactose feeding to induce hyperhexosemia for 8 wk starting at 6 wk of age. We investigated FN mRNA, EDB⁺FN mRNA, and transforming growth factor (TGF)- mRNA expression, Akt phosphorylation, Akt kinase activity, and NF-B and AP-1 activation in the retina, heart, and kidney. Renal and cardiac tissues were histologically examined. Galactose feeding caused significant upregulation of FN, EDB⁺FN, and TGF- in all tissues. FN protein levels paralleled mRNA. Such upregulation were prevented in Akt1-deficient galactose-fed mice. Galactose feeding caused ECM protein deposition in the glomeruli and in the myocardium, which was prevented in the Akt knockout mice. NF-B and AP-1 activation was pronounced in galactose-fed wild-type mice and prevented in the galactose-fed Akt1/PKB-deficient group. In the retina and kidney, Ser473 was the predominant site for Akt phosphorylation, whereas in the heart it was Thr308. Parallel experiment in streptozotocin-induced diabetic animals showed similar results. The data from this study indicate that hyperhexosemia-induced Akt/PKB activation may be an important mechanism leading to NF-B and AP-1 activation and increased ECM protein synthesis in the organs affected by chronic diabetic complications.

protein kinase B; galactose; EDB⁺ fibronectin; transcription factors; knockout mouse

This article has been cited by other articles:

				B. Feng, S. Chen, J. Chiu, B. George, and S. Chakrabarti Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1119 - E1126. [Abstract] [Full Text] [PDF]