TACE-dependent EGF receptor activation in angiotensin-II-induced kidney disease.

Angiotensin II (Ang II) has been implicated in the development of cardiovascular disorders and chronic kidney disease (CKD). Ang II causes renal lesions through the activation of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, also called a disintegrin and a metalloproteinase domain 17) and the release of transforming growth factor (TGF)-alpha, which binds to and activates the epidermal growth factor receptor. Renal lesions such as glomerulosclerosis, tubular atrophy, fibrosis, mononuclear cell infiltration and proteinuria following chronic Ang II infusion are substantially reduced in mice lacking TGF-alpha and those given a specific TACE inhibitor. These findings indicate that the selective inhibition of renal TACE could have therapeutic potential in the treatment of CKD.