Circulating Matrix Metalloproteinase-2 Is an Independent Correlate of Proteinuria in Patients with Chronic Kidney Disease

Nagano, Makio; Fukami, Kei; Yamagishi, Sho‐ichi; Ueda, Seinosuke; Kaida, Yusuke; Matsumoto, Takafumi; Yoshimura, Junko; Hazama, Takuma; Takamiya, Yoshimi; Kusumoto, Tetsuya; Gohara, Shojiro; Tanaka, Hideharu; Adachi, Hisashi; Okuda, Seiya

doi:10.1159/000151439

Cited by 26 publications

(19 citation statements)

References 57 publications

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“…With respect to MMP-2, our data are consistent with previous reports showing that circulating MMP-2 levels are elevated in predialysis CKD 21 and are higher in those with cardiovascular comorbidity. 21,22 MMP-2 levels have also previously been strongly associated with APWV in a hypertensive but otherwise healthy cohort.…”

Section: Discussionsupporting

confidence: 92%

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Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

et al. 2012

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Abstract-In the large conduit arteries, elastin is important in maintaining vascular compliance. Studies in animal models suggest that elastin degradation may promote arteriosclerotic vascular changes. There is already a well-established link between aortic stiffening and mortality in the general population and in patients undergoing dialysis. Elastin degradation is mediated by several proteases, including matrix metalloproteinase 2 and cathepsin S. Elastin turnover may be inferred by measuring serum levels of elastin-derived peptides. We analyzed the serum concentration of these biomarkers, their endogenous inhibitors, and aortic pulse wave velocity in 200 patients with stages 3 and 4 chronic kidney disease and then serially in a subgroup of 65 patients over 36 months. Serum matrix metalloproteinase 2, cathepsin S, and elastin-derived peptide levels were independently associated with baseline aortic pulse wave velocity and changes in stiffness over the follow-up period. Higher matrix metalloproteinase 2 and elastin-derived peptide levels were also independently associated with preexisting cardiovascular disease. In multivariable Cox regression, higher serum elastin-derived peptide levels were independently associated with increased all-cause mortality (hazard ratio per SD increaseϭ1.78; Pϭ0.021). In predialysis chronic kidney disease, elastin degradation is an important determinant of arterial stiffness and is associated with all-cause mortality. 1 Loss of elastin leads to an increase in the collagen:elastin ratio and augmented mechanical loading of stiffer collagen fibers. With age, vascular smooth muscle cells (VSMCs) become less contractile, and there are increased rates of cellular senescence and death.2 Together, these changes contribute to the loss of intrinsic elasticity and progressive stiffening of the arterial wall.3 In addition to promoting arteriosclerosis, elastin degradation also stimulates intimal VSMC invasion, neointima formation, and plaque destabilization and, thus, may also be an important factor in the pathogenesis of atherosclerotic disease. Age-associated arterial remodeling is accelerated in patients with chronic kidney disease (CKD), who have a vastly elevated cardiovascular risk compared with the general population. 5 Although not a universal finding, arterial stiffness, as measured by various methods, has been associated with decline in renal function in patients with CKD 6-8 and is a strong predictor of cardiovascular risk and all-cause mortality in patients with end-stage renal failure 9 and in non-CKD populations. 10Extracellular matrix turnover is mediated by a number of elastolytic proteinases, including Zn 2ϩ /Ca 2ϩ -dependent matrix metalloproteinases (MMPs; eg, MMP-2) and cathepsin cysteine proteases, such as cathepsin S. These proteases are mainly secreted by activated macrophage, resident myofibroblasts, or VSMCs but are also expressed intracellularly in a wide range of cell types. 4 The activities of MMP-2 and cathepsin S are partly regulated by the concentration of endog...

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Section: Discussionsupporting

confidence: 92%

“…21,22 MMP-2 levels have also previously been strongly associated with APWV in a hypertensive but otherwise healthy cohort. 23 Similarly, existing data on EDPs indicate a strong correlation with age and history of CVD.…”

Section: Discussionmentioning

confidence: 89%

Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

et al. 2012

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“…This is in agreement with our previous study, where we observed the association between MMP-2 and IMT, a surrogate marker of CVD in hemodialyzed patients. Recently, Nagano et al [23] also found that serum MMP-2 levels were positively associated with IMT and the presence of atherosclerotic plaque in the carotid artery in non-dialyzed CKD patients.…”

Section: Discussionmentioning

confidence: 99%

Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients

Pawlak¹,

Tankiewicz

Myśliwiec

et al. 2010

Nephron Clin Pract

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Background/Aims: Matrix metalloproteinases (MMPs), their inhibitors (TIMPs), oxidative stress (SOX) and kynurenine (KYN) pathway have been postulated in cardiovascular disease (CVD) progression. We hypothesized the possible association between the MMP/TIMP system, KYNs and CVD prevalence in continuous ambulatory peritoneal dialysis (CAPD) patients. Methods: We assessed MMP-2, MMP-9, TIMP-1, TIMP-2, KYN and its metabolite – quinolinic acid (QA), and SOX marker – Cu/Zn superoxide dismutase (Cu/Zn SOD) levels in CAPD patients both with and without CVD and healthy controls. Results: MMP-2, TIMP-2, Cu/Zn SOD, KYN and QA were significantly higher in CAPD patients with CVD than in patients without CVD and controls. MMP-2 and TIMP-2 were positively correlated with QA and Cu/Zn SOD levels, and the strong association was between MMP-2 and TIMP-2 levels. Multiple regression analyses identified Cu/Zn SOD, TIMP-2, QA and QA/KYN ratio as the factors independently associated with MMP-2, whereas MMP-2 and Cu/Zn SOD were independent variables affecting TIMP-2 levels. Conclusions: MMP-2 and TIMP-2 concentrations were higher in CAPD patients with CVD than in patients without CVD and healthy controls. Upregulation of the MMP-2/TIMP-2 system was associated with QA levels and increased oxidative status, suggesting the connection between KYN pathway activation, arterial remodeling and CVD prevalence in uremic patients on CAPD treatment.

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“…MMP-9 was fond by us to mediate EMT of the tubular epithelial cells downstream of TGF-β [15,16] . A previous report has shown that serum levels of MMP-2 were correlated with proteinuria, intima media thickness and reduced kidney function in patients with CKD [24] . Plasma concentration of MMP-9 was found to be increased in the early stage of diabetic kidney disease [14] .…”

Section: Mmps and Inflammation In Ckdmentioning

confidence: 91%

Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

Zhao

Dong²,

Tian³

et al. 2013

WJN

120

104

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Matrix metalloproteinases (MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial-mesenchymal transition (EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT) and pericyte-myofibroblast transdifferentiation.

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Circulating Matrix Metalloproteinase-2 Is an Independent Correlate of Proteinuria in Patients with Chronic Kidney Disease

Cited by 26 publications

References 57 publications

Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients

Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

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