While past studies demonstrated decreased renal MMP activity in Type 1 diabetes and in mesangial cells grown under high glucose conditions, renal MMP expression/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/activity of MMPs in Type 2 diabetic Goto-Kakizaki (GK) rats treated with vehicle or ET_A receptor selective antagonist ABT-627 for 4 weeks were assessed by gelatin zymography, fluorogenic gelatinase assay and immunoblotting. In addition, expression/phosphorylation of epidermal growth factor receptor (EGFR) and connective tissue growth factor was 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. A 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/expression. Histological analysis of kidneys did not reveal any structural changes. Phosphorylation of epidermal growth factor receptor (EGFR~P) 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 up-regulation of renal MMPs in the absence of any kidney damage. While 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.