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.