HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 286/2/F409    most recent 00007.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Singh, L. P. Articles by Crook, E. D. Search for Related Content PubMed PubMed Citation Articles by Singh, L. P. Articles by Crook, E. D.

Hexosamines and TGF-₁ use similar signaling pathways to mediate matrix protein synthesis in mesangial cells

Department of Internal Medicine, Division of Nephrology, Wayne State University School of Medicine and the John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201

Submitted 8 January 2003 ; accepted in final form 6 October 2003

Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix (ECM) protein accumulation are seen in diabetic glomerulopathy. Transforming growth factor-₁ (TGF-₁) mediates high-glucose-induced matrix production in the kidney. Recent studies demonstrated that some of the effects of high glucose on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP) in which fructose-6-phosphate is converted to glucosamine (GlcN) 6-phosphate. We previously showed that the high-glucose-mediated fibronectin and laminin synthesis in MES cells is mediated by the HBP and that GlcN is more potent than glucose in inducing TGF-₁ promoter luciferase activity. In this study, we investigated the hypothesis that the effects of glucose on MES matrix production occur via hexosamine regulation of TGF-₁. Culturing simian virus (SV)-40-transformed rat kidney MES cells in 25 mM glucose (HG) for 48 h increases cellular fibronectin and laminin levels about twofold on Western blots compared with low glucose (5 mM). GlcN (1.5 mM) or TGF-₁ (2.5-5 ng/ml) for 24-48 h also increases ECM synthesis. However, the effects of HG or GlcN with TGF-₁ are not additive. The presence of anti-TGF-₁ antibodies (20 µg/ml) blocks both TGF-₁- and GlcN-induced fibronectin synthesis. TGF-₁ increased ECM levels via PKA (laminin and fibronectin) and PKC (fibronectin) pathways. Similarly, TGF-₁ and hexosamines led to nonadditive increases in phosphorylation of the cAMP responsive element binding transcription factor. These results suggest that the effects of excess glucose on MES ECM synthesis occur via HBP-mediated regulation of TGF-₁.

diabetic nephropathy; hexosamine pathway; transforming growth factor-; extracellular matrix protein; cell signaling

This article has been cited by other articles:

				H. Yang, C. J. Lee, L. Zhang, M. D. Sans, and D. M. Simeone Regulation of transforming growth factor {beta}-induced responses by protein kinase A in pancreatic acinar cells Am J Physiol Gastrointest Liver Physiol, July 1, 2008; 295(1): G170 - G178. [Abstract] [Full Text] [PDF]

				M.-C. Battista, C. Roberge, M. Otis, and N. Gallo-Payet Seladin-1 expression in rat adrenal gland: effect of adrenocorticotropic hormone treatment J. Endocrinol., January 1, 2007; 192(1): 53 - 66. [Abstract] [Full Text] [PDF]