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

Vera Portik-Dobos, Alex K. Harris, Weiwei Song, Jimmie Hutchinson, Maribeth H Johnson, John D. Imig, David M. Pollock, Adviye Ergul

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Abstract

Although past studies havedemonstrated 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume290
Issue number2
DOIs
StatePublished - Feb 1 2006

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Endothelins
Matrix Metalloproteinases
Epidermal Growth Factor Receptor
Transcriptional Activation
Kidney
Endothelin-1
Immunoblotting
Type 2 Diabetes Mellitus
Phosphorylation
Matrix Metalloproteinase 14
Connective Tissue Growth Factor
Gelatinases
Mesangial Cells
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Diabetes Complications
Gelatin
Type 1 Diabetes Mellitus
Fibronectins
Up-Regulation

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes. / Portik-Dobos, Vera; Harris, Alex K.; Song, Weiwei; Hutchinson, Jimmie; Johnson, Maribeth H; Imig, John D.; Pollock, David M.; Ergul, Adviye.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 290, No. 2, 01.02.2006.

Research output: Contribution to journalArticle

Portik-Dobos, Vera ; Harris, Alex K. ; Song, Weiwei ; Hutchinson, Jimmie ; Johnson, Maribeth H ; Imig, John D. ; Pollock, David M. ; Ergul, Adviye. / Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2006 ; Vol. 290, No. 2.
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