Kidney International, Vol. 61 (2002), pp. 1174–1175

EDITORIAL

Protease mediated tubular injury: A new direction in acuterenal failure?

In this issue of Kidney International, Carmago, Shah, after that, Trachtman et al reported that following eitherbilateral renal artery clamping or glycerol-induced actuteand Walker present evidence that meprin A, a metallo-renal failure, mouse strains exhibiting normal meprin ac-protease present in the brush-border of tubular epithelialtivity developed more severe renal structural and func-cells, plays a key role in hypoxic/ischemic acute renaltional injury than mouse strains with low meprin activitytubular injury in rats [1]. This is an exciting observation[6]. Subsequently Walker, Kaushal, and Shah demon-that may signal a new direction in the pathogenesis ofstrated that meprin A could cleave the basement mem-acute renal failure.brane component nidogen [7]. They also reported thatMeprin is an acronym for metallo-peptidase from re-following renal ischemia-reperfusion in rats, meprin Anal tissue [reviewed in 2, 3]. The enzyme was first isolatedundergoes a translocation from the tubular brush-borderby Bond et al from tubular brush-border membranesmembrane to the cytoplasm and tubular basement mem-prepared from kidneys of BALB/c mice. Two isoformsbrane. In the current paper, Carmago, Shah, and Walkerof meprin have been identified, meprin A and meprinfirst demonstrate that exogenously added meprin is cyto-B, that exhibit significant differences in amino acid com-toxic to porcine proximal tubular cells (LLC-PK1) andposition, catalytic activity, and substrate specificity. BothMadin-Darby canine kidney (MDCK) cells in culture. In-meprins exist as disulfide-linked, oligomeric, membrane-terestingly, this toxicity is not mediated by cell detach-bound, glycoproteins containing one zinc atom and threement. They then show that kidney slices (used becausecalcium ions per 85 kD subunit. Meprin A (the bettercultured renal cell lines do not express meprin) are pro-characterized and more active isoform) is able to degradetected from hypoxia-reoxygenation injury by the specifica variety of biologically active peptides and proteins po-meprin inhibitor, actinonin. Finally, and most exciting, istentially relevant to renal injury, including �-atrial natri-their observation that treatment of rats with actinoninuretic peptide transforming growth factor (TGF-�), en-provides both histological and functional protection of thedothelin I, big endothelin I, bradykinin, and angiogensinkidney following 40 minutes of renal ischemia. TakenI and II. Meprins are inhibited by the classical inhibitorstogether, these studies provide convincing evidence for aof metalloproteinases such as ethylenediaminetetraace-pathogenic role for meprin A in hypoxic/ischemic acutetic acid (EDTA) but not by inhibitors of serine, cysteine,renal tubular injury in rats.or aspartic proteinases. Important for this discussion, the

As with most good research, this study raises morenaturally occurring peptide hydroxamate, actinonin, is a questions than it answers. For basic scientists, the primarypotent inhibitor of rat meprin A. question is, how does meprin mediate its cytotoxic effects?

The first hint that meprin might play an important role One possibility is the degradation of some protein orin renal pathophysiology appeared in 1985, when Bey- peptide critical for tubular cell function or survival. In thisnon and Bond reported that the kidney is the only major light, the ability of meprin A to degrade endothelin, atrialorgan that exhibits significant meprin activity [4]. Impor- natriuretic peptide, TGF-�, angiotensin I and II, and bra-tantly, human kidney does contain meprin, albeit at lower dykinin might be considered. Perhaps the shift of meprinlevels than rat or mouse kidney. The story unfolds nicely from the tubular brush-border to the basement membranefrom there, although with an interval of nearly 10 years. impedes tubular regeneration and repair by degradationIn 1994, Kaushal, Walker, and Shah purified a matrix- of one or more components of the extracellular matrix.degrading, 350 kD, neutral metalloproteinase from rat Alternatively, meprin could produce a cytotoxic peptide.kidney cortex [5]. Surprisingly, amino acid sequence deter- These and other possible mechanisms will no doubt bemination of the N-terminal and two internal fragments of examined, hopefully in the near future. Additional impor-the purified proteinase showed it to be identical to the tant questions for clinical nephrologists include the follow-meprin A subunit. In addition, they reported that meprin ing: Does inhibition of meprin attenuate the reduction inis the major neutral endopeptidase in rat kidney, account- renal function associated with ischemia-reperfusion injurying for 5% or more of the total tubular protein. Shortly in humans? Does meprin-mediated cytotoxicity contrib-

ute to other types of acute renal injury? If the answer toeither of these questions is “yes,” then meprin could beKey words: meprin, protease-mediated injury, actinonin, metallopro-

tease, acute renal failure. a lucrative target for therapeutic intervention in such pa-thologies. 2002 by the International Society of Nephrology

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Editorial 1175

The path from the lab bench to the bedside is littered REFERENCESwith promising ideas that ultimately did not play out. 1. Carmago S, Shah SV, Walker PD: Meprin, a brush-border enzyme,Clearly, the jury is still out on the role of meprin and the plays an important role in hypoxic/ischemic acute renal tubular injury

in rats. Kidney Int 61:959–966, 2002therapeutic potential of meprin inhibitors in acute renal2. Bond JS, Beynon RJ: Meprin: A membrane-bound metallo-endo-failure. However, to paraphrase the protagonist in Mary peptidase. Curr Top Cellular Reg 28:263–290, 1986

Shelly’s famous novel, Frankenstein, “Good science, how- 3. Wolz RL, Bond JS: Meprins A and B. Methods Enzymology 248:325–345, 1995ever erroneously directed, scarcely ever fails in ultimately

4. Beynon RJ, Bond JS: In Intracellular Protein Catabolism, Kahai-turning to the solid advantage of mankind.” I look forward rallah EA, Bond JS, Bird JWC, eds., pp 185–194, Liss, Newto reading about the “solid advantages” that I predict will York, 1985

5. Kaushal GP, Walker PD, Shah SV: An old enzyme with a newresult from the continuation of this interesting and excitingfunction: purification and characterization of a distinct matrix-work.degrading metalloproteinase in rat kidney cortex and its identi-fication as meprin. J Cell Biol 126:1319–1327, 1994William H. Baricos

6. Trachtman H, Valderrama E, Dietrich JM, Bond JS: The roleNew Orleans, Louisianaof meprin A in the pathogenesis of acute renal failure. BiochemBiophys Res Comm 208:498–505, 1995Correspondence to William H. Baricos, Ph.D., Department of Bio-

7. Walker PD, Kaushal GP, Shah SV: Meprin A, the major matrixchemistry SL 43, Tulane University Health Sciences Center, 1430 Tulanedegrading enzyme in renal tubules, produces a novel nidogen frag-Avenue, New Orleans, LA 70112, USA.ment in vitro and in vivo. Kidney Int 53:1673–1680, 1998E-mail: baricosw@tulane.edu