Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 19, Pages 13308-13322Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.559088
Keywords
ADAM ADAMTS; Kidney; Metalloprotease; Mouse; Shedding; siRNA; ADAM10; ADAM17; Meprin
Categories
Funding
- National Institutes of Health [R01 DK081690]
- Veterans Affairs Merit Awards [BX000538, BX000828]
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Background: Meprin A is a membrane-associated metalloproteinase in proximal tubules that plays an important role in acute kidney injury (AKI). Results: In ischemia-reperfusion injury, meprin A is shed from the membranes, and ADAM10 was identified as the major sheddase. Conclusion: ADAM10 is the major sheddase involved in the release of meprin A. Significance: These studies identify ADAM10 as a potential therapeutic target for AKI. Meprin A, composed of and 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 alone and both meprin and meprin for the expression of meprin A. Phorbol 12-myristate 13-acetate and ionomycin stimulated ectodomain shedding of meprin and meprin A. Among the inhibitors of various proteases, the broad spectrum inhibitor of the ADAM family of proteases, tumor necrosis factor- protease inhibitor (TAPI-1), was most effective in preventing constitutive, phorbol 12-myristate 13-acetate-, and ionomycin-stimulated shedding of meprin 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 and meprin A shedding. Furthermore, overexpression of ADAM10 resulted in enhanced shedding of meprin from both transfectants. Our studies demonstrate that ADAM10 is the major ADAM metalloproteinase responsible for the constitutive and stimulated shedding of meprin and meprin A. These studies further suggest that inhibiting ADAM 10 activity could be of therapeutic benefit in AKI.
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