Targeted disruption of the meprin metalloproteinase β gene protects against renal ischemia-reperfusion injury in mice

Abstract

Meprins are membrane-bound and secreted metalloproteinases consisting of alpha- and/or beta-subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin alpha/beta-isoform is deleterious when renal tissue is subjected to ischemia-reperfusion (I/R). To delineate the roles of the meprin isoforms in renal disease, we subjected mice deficient in meprin-beta (KO) and their wild-type (WT) counterparts to I/R. WT mice were markedly more susceptible to renal injury after I/R than the meprin-beta KO mice as determined by blood urea nitrogen levels. Urinary levels of inflammatory cytokines IL-6 and KC (CXCL1) were significantly higher in WT compared with meprin-beta KO mice by 6 h post-I/R. At 96 h postischemia, kidney mRNA expression levels for tumor necrosis factor-alpha, transforming growth factor-beta, inducible nitric oxide synthase, and heat shock protein-27 were significantly higher in the WT than meprin-beta KO mice. For WT mice subjected to I/R, there was a rapid (3 h) redistribution of meprin beta-subunits in cells in S3 segments of proximal tubules, followed by shedding of apical cell membrane and detachment of cells. These studies indicate that meprin-beta is important in the pathogenesis of renal injury following I/R and that the redistribution of active meprin-alpha/beta is a major contributor to renal injury and subsequent inflammation.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Meprin subunits a and b cleave a variety of biologically active peptides; in particular, we want to point out gastrin and cholecystokin on one side (which are substrates for meprin b) and substance P and many cytokines on the other side (which are substrates for meprin a, see Sterchi et al, 2008). Meprins are expressed abundantly in epithelial cells of kidney, intestine and skin and recently a number of studies indicate their potential functions in pathological conditions, such as acute and chronic renal failures, diabetic nephropathy, colon carcinoma (Bylander et al, 2008;Lottaz et al, 1999;Red Eagle et al, 2005).…”

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

“…These studies reported that several factors that exacerbate renal disease, such as kidney injury molecule-1, monocyte chemoattractant protein-1, meprin, and osteopontin, could serve as biomarkers for injury of the proximal tubule (PT) epithelium, progression of DN, renal ischemiareperfusion injury, and focal segmental glomerulosclerosis, respectively. [3][4][5][6] Typically, in order to discover new biomarkers, a comprehensive analysis of the genes that are upregulated in these diseases is essential. 7 Microarray is a very useful analytical method; however, a large number of the relevant genes might be affected by the genetic background of the patients and/or systemic diseases.…”

The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase

“…Meprins hydrolyze a wide variety of peptides and proteins, such as growth factors, peptide hormones, and extracellular matrix proteins (11); however, their precise physiological role is not clear. The role of meprins has been studied in renal diseases, inflammation, and angiogenesis (4,10,20,27,38). It has been reported that meprin-␤ exacerbated the acute kidney injuries, whereas meprin-␣ was reported to be beneficial (10,20).…”

“…The role of meprins has been studied in renal diseases, inflammation, and angiogenesis (4,10,20,27,38). It has been reported that meprin-␤ exacerbated the acute kidney injuries, whereas meprin-␣ was reported to be beneficial (10,20). Meprin-␣ displayed proangiogenic properties in cell culture settings and in animal models (27,38).…”

“…These peptides are the expected products of the T␤4 hydrolysis at the predicted meprin-␣ cleavage sites at E 21 -T 22 and E 24 -K 25 (41). In addition, data from mass spectrometry revealed two new putative cleavage sites at D 13 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] ; mass: 2,279.20 Da). This is consistent with the specificity of the active site of meprin-␣, which prefers acidic amino acids at positions near and adjacent to its cleavage site (20,21).…”