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: 290/2/R435    most recent 00300.2005v1 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 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 Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Portik-Dobos, V. Articles by Ergul, A. Search for Related Content PubMed PubMed Citation Articles by Portik-Dobos, V. Articles by Ergul, A.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes

¹Program in Clinical and Experimental Therapeutics, University of Georgia, College of Pharmacy, ²Department of Biostatistics, and ³Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

Submitted 28 April 2005 ; accepted in final form 14 October 2005

Although past studies have demonstrated decreased renal matrix metalloproteinase (MMP) activity in type 1 diabetes and in mesangial cells grown under high glucose conditions, renal MMP expression and activity in type 2 diabetes and the regulation of MMPs by profibrotic factors involved in diabetic renal complications such as endothelin-1 (ET-1) remained unknown. The renal expression and activity of MMPs in type 2 diabetic Goto-Kakizaki (GK) rats treated with vehicle or ET_A receptor selective antagonist ABT-627 for 4 wk were assessed by gelatin zymography, fluorogenic gelatinase assay, and immunoblotting. In addition, expression and phosphorylation of epidermal growth factor receptor (EGFR) and connective tissue growth factor were evaluated by immunoblotting. Renal sections stained with Masson trichrome were used to investigate kidney structure. MMP-2 activity and protein levels were significantly increased in both cortical and medullary regions in the GK rats. Membrane-bound MMP (MT1-MMP), MMP-9, and fibronectin levels were also increased, and ABT-627 treatment did not have an effect on MMP activity and expression. Histological analysis of kidneys did not reveal any structural changes. Phosphorylation of EGFR was significantly increased in the diabetic animals, and ABT-627 treatment prevented this increase, suggesting ET-1-mediated transactivation of EGFR. These results suggest that there is early upregulation of renal MMPs in the absence of any kidney damage. Although the ET_A receptor subtype is not involved in the early activation of MMPs in type 2 diabetes, ET-1 contributes to transactivation of growth-promoting and profibrotic EGFR.

This article has been cited by other articles:

				J. M. Catania, G. Chen, and A. R. Parrish Role of matrix metalloproteinases in renal pathophysiologies Am J Physiol Renal Physiol, March 1, 2007; 292(3): F905 - F911. [Abstract] [Full Text] [PDF]