| First Author | Herzog C | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 19 | Pages | 13308-22 |
| PubMed ID | 24662289 | Mgi Jnum | J:217238 |
| Mgi Id | MGI:5613431 | Doi | 10.1074/jbc.M114.559088 |
| Citation | Herzog C, et al. (2014) ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A. J Biol Chem 289(19):13308-22 |
| abstractText | Meprin A, composed of alpha and beta subunits, is a membrane-bound metalloproteinase in renal proximal tubules. Meprin A plays an important role in tubular epithelial cell injury during acute kidney injury (AKI). The present study demonstrated that during ischemia-reperfusion-induced AKI, meprin A was shed from proximal tubule membranes, as evident from its redistribution toward the basolateral side, proteolytic processing in the membranes, and excretion in the urine. To identify the proteolytic enzyme responsible for shedding of meprin A, we generated stable HEK cell lines expressing meprin beta alone and both meprin alpha and meprin beta for the expression of meprin A. Phorbol 12-myristate 13-acetate and ionomycin stimulated ectodomain shedding of meprin beta and meprin A. Among the inhibitors of various proteases, the broad spectrum inhibitor of the ADAM family of proteases, tumor necrosis factor-alpha protease inhibitor (TAPI-1), was most effective in preventing constitutive, phorbol 12-myristate 13-acetate-, and ionomycin-stimulated shedding of meprin beta and meprin A in the medium of both transfectants. The use of differential inhibitors for ADAM10 and ADAM17 indicated that ADAM10 inhibition is sufficient to block shedding. In agreement with these results, small interfering RNA to ADAM10 but not to ADAM9 or ADAM17 inhibited meprin beta and meprin A shedding. Furthermore, overexpression of ADAM10 resulted in enhanced shedding of meprin beta from both transfectants. Our studies demonstrate that ADAM10 is the major ADAM metalloproteinase responsible for the constitutive and stimulated shedding of meprin beta and meprin A. These studies further suggest that inhibiting ADAM 10 activity could be of therapeutic benefit in AKI. |
