Meprin A metalloproteinase and its role in acute kidney injury

Abstract

Meprin A, composed of α- and β-subunits, is a membrane-associated neutral metalloendoprotease that belongs to the astacin family of zinc endopeptidases. It was first discovered as an azocasein and benzoyl-l-tyrosyl-p-aminobenzoic acid hydrolase in the brush-border membranes of proximal tubules and intestines. Meprin isoforms are now found to be widely distributed in various organs (kidney, intestines, leukocytes, skin, bladder, and a variety of cancer cells) and are capable of hydrolyzing and processing a large number of substrates, including extracellular matrix proteins, cytokines, adherens junction proteins, hormones, bioactive peptides, and cell surface proteins. The ability of meprin A to cleave various substrates sheds new light on the functional properties of this enzyme, including matrix remodeling, inflammation, and cell-cell and cell-matrix processes. Following ischemia-reperfusion (IR)- and cisplatin-induced acute kidney injury (AKI), meprin A is redistributed toward the basolateral plasma membrane, and the cleaved form of meprin A is excreted in the urine. These studies suggest that altered localization and shedding of meprin A in places other than the apical membranes may be deleterious in vivo in acute tubular injury. These studies also provide new insight into the importance of a sheddase involved in the release of membrane-associated meprin A under pathological conditions. Meprin A is injurious to the kidney during AKI, as meprin A-knockout mice and meprin inhibition provide protective roles and improve renal function. Meprin A, therefore, plays an important role in AKI and potentially is a unique target for therapeutic intervention during AKI.

Cellular and Molecular Mechanisms of AKI

“…In addition, there are four potential mechanisms by which the plasma membrane can play an important role in AKI that could be fruitful subjects for further research: by alterations in (1) membrane composition, (2) membrane-associated proteins, and (3) membrane-associated enzymatic activity, and by (4) signaling by membrane-associated components. Examples for each of these potential roles for the plasma membrane in AKI include the following: (1) the composition of cholesterol-rich microdomains is altered after AKI, and lipid microdomains are important both for preventing cell injury and developing subsequent cytoresistance to further insult 1,2 ; (2) there is increased expression of FAS ligand, 3 altered caveolin-1 expression, 4,5 and decreased Na transporters after AKI 6 ; (3) decreased membrane-associated alkaline phosphatase 7 and altered expression of the zinc-dependent metalloproteinase meprin A are associated with AKI 8 ; and (4) a potential role has been suggested for microvesicles/exosomes in protection and recovery from AKI. 9,10 Recent studies have highlighted the importance of regulated necrosis or necroptosis, a receptor-interacting protein kinase-dependent necrotic cell death in AKI.…”

Understanding the Exacerbating Role of the Metalloproteinase Meprin during AKI, an <i>In Silico</i> Approach

“…The predicted ligand/substrate binding site of meprin α obtained using 3DLigandSite and the 18 binding pockets for meprin α as detected by DoGSiteScorer is shown in Figure 4 and Figure 5. The critical amino acids in the active sites of Meprin alpha for substrate and peptide bond specificity, interpreted from the in silico protein cavity, active site prediction results and literature studies [8,22] were concluded as follows:…”

“…Meprins has the ability to degrade components of extracellular matrix (ECM) proteins, process pro inflammatory cytokines, adherens junction proteins and hormones. It indicates that the functional properties of the enzyme might be toxic during the pathological condition of AKI [8,9].…”

“…Figure 1 shows that meprin subunits are bound together by disulfide bridges (horizontal black bars). Meprin A (α2β2 or α3β1) is bound to the brush-border membrane via the meprin β subunit and is called as the membrane bound meprin A. Meprin A that is not bound to the β subunit is secreted as a homooligomer and is called as the secreted meprin A [8]. The present study did in silico protein tertiary structure prediction to decipher the α subunit of meprin and then identified its critical amino acids, cavities and active sites.…”

“…Both of them share 42% identity in amino acid sequences [7]. Kidney meprin A is a homooligomer of α subunits, or a heterooligomer of α and β subunits, whereas kidney meprin B is a homooligomer of β subunits [8]. Figure 1 shows that meprin subunits are bound together by disulfide bridges (horizontal black bars).…”