ADAM10 Is the Major Sheddase Responsible for the Release of Membrane-associated Meprin A

摘要: Meprin A, composed of α and β subunits, is a membrane-bound metalloproteinase in renal proximal tubules. A plays an important role tubular epithelial cell injury during acute kidney (AKI). The present study demonstrated that ischemia-reperfusion-induced AKI, meprin was shed from tubule membranes, as evident its redistribution toward the basolateral side, proteolytic processing excretion urine. To identify enzyme responsible for shedding we generated stable HEK lines expressing alone both expression A. Phorbol 12-myristate 13-acetate ionomycin stimulated ectodomain Among inhibitors various proteases, broad spectrum inhibitor ADAM family tumor necrosis factor-α protease (TAPI-1), most effective preventing constitutive, phorbol 13-acetate-, ionomycin-stimulated medium transfectants. use differential ADAM10 ADAM17 indicated inhibition sufficient to block shedding. In agreement with these results, small interfering RNA but not ADAM9 or inhibited Furthermore, overexpression resulted enhanced Our studies demonstrate major constitutive These further suggest inhibiting 10 activity could be therapeutic benefit AKI.