Application of Antibody Array Technology in the Analysis of Urinary Cytokine Profiles in Patients with Chronic Kidney Disease

Liu, Bi‐Cheng; Zhang, Lu; Lv, Lin‐Li; Wang, Yanli; Liu, Diange; Zhang, Xiaoliang

doi:10.1159/000096871

Cited by 55 publications

(28 citation statements)

References 40 publications

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“…39,40 Like the tubular injury markers, UK-396082 reduced urinary levels of TG2 compared with vehicle control, supporting the notion that one of the beneficial effects of TAFI blockade was on ECM turnover. Elevated serum and urinary TIMP-1 has also been associated with the progression of CKD 41,42 and renal injury, 43 and indeed urine TIMP-1 increased after SNx. However, in contrast to TG2, KIM-1, and NGAL, TIMP-1 increased with UK-396082 therapy.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Atkinson

Pullen

Silva-Lodge

et al. 2015

Journal of the American Society of Nephrology

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Uncontrolled diabetes, inflammation, and hypertension are key contributors to progressive renal fibrosis and subsequent loss of renal function. Reduced fibrinolysis appears to be a feature of ESRD, but its contribution to the fibrotic program has not been extensively studied. Here, we show that in patients with CKD, the activity levels of serum thrombin-activated fibrinolysis inhibitor and plasmin strongly correlated with the degree of renal function impairment. We made similar observations in rats after subtotal nephrectomy and tested whether pharmacologic inhibition of thrombin-activated fibrinolysis inhibitor with UK-396082 could reduce renal fibrosis and improve renal function. Compared with untreated animals, UK-396082-treated animals had reduced glomerular and tubulointerstitial fibrosis after subtotal nephrectomy. Renal function, as measured by an increase in creatinine clearance, was maintained and the rate of increase in proteinuria was reduced in UK-396082-treated animals. Furthermore, cumulative survival improved from 16% to 80% with inhibition of thrombin-activated fibrinolysis inhibitor. Taken together, these data support the importance of the fibrinolytic axis in regulating renal fibrosis and point to a potentially important therapeutic role for suppression of thrombin-activated fibrinolysis inhibitor activity.

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Section: Discussionmentioning

confidence: 98%

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Atkinson

Pullen

Silva-Lodge

et al. 2015

Journal of the American Society of Nephrology

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“…Therefore, so far, most investigations of MMP-2 have been limited to renal development, renal tubular physiology and glomerular pathophysiology. Measurements of MMP-2 are mainly performed in the circulation and renal biopsy specimens [13, 18,20,21,22,23]. The altered regulation of MMP-2 in the vasculature may be crucial in linking the progression of CKD to cardiovascular disease, but has never been tested.…”

Section: Discussionmentioning

confidence: 99%

Increased Matrix Metalloproteinase 2 Activity in the Human Internal Mammary Artery Is Associated with Ageing, Hypertension, Diabetes and Kidney Dysfunction

Chung¹,

Booth

Rose

et al. 2008

J Vasc Res

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Dysregulation of matrix metalloproteinase (MMP)-2 in the vasculature has been suggested to be associated with increased prevalence of cardiovascular disease and renal injury. In this descriptive study, we hypothesized that arterial MMP-2 activity is elevated in the presence of cardiovascular risk factors such as diabetes, hypertension, smoking and ageing, and that it correlates with the degree of kidney function. MMP-2 activity in internal mammary arteries (n = 37) was measured using gelatinolytic zymography, and cutoffs were determined using sample-derived medians. Patient demographics and clinical data were analyzed, and the estimated glomerular filtration rate (eGFR) was calculated. High MMP-2 activity (>60,000 units) was associated with age, hypertension and diabetes (p = 0.0034, 0.06 and 0.0034, respectively). Multivariate analysis showed that age and diabetes were independent predictors of high MMP-2 activity. There is a trend towards increased MMP-2 activity and reduced eGFR (p = 0.010). The current exploratory work describes that the activity of MMP-2 in the internal mammary artery is correlated with age, hypertension, diabetes and eGFR. It is the first report suggesting that MMP-2 in the arterial vasculature could be the possible mediator crucial in linking the progression of kidney function to cardiovascular disease.

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“…Progression to end-stage kidney disease is paralleled by the accumulation of ECM, leading to fibrosis and sclerosis [12]. Increased expression or activity of MMPs has been described in cases of several different glomerular diseases such as IgA nephropathy [13], membranous glomerulonephritis [12], ANCA-associated glomerulonephritis [14], early diabetic nephropathy [15] and chronic kidney disease [16] in humans. In renal disease the timing of altered MMP activity appears to be crucial to determining whether the activity will have a beneficial or detrimental effect on renal integrity [17].…”

Section: Introductionmentioning

confidence: 99%

TNF-Alpha and IL-1Beta-Mediated Regulation of MMP-9 and TIMP-1 in Human Glomerular Mesangial Cells

Nee¹,

Tuite²,

Ryan³

et al. 2007

Nephron Exp Nephrol

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Background: Renal cells such as mesangial cells are known to secrete metalloproteinases that are capable of degrading the constituents of the glomerular basement membrane (GBM). Disruption of the GBM via cytokine-induced alterations in matrixmetalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may be an important mechanism in the renal disease process. In renal disease, both resident renal cells and infiltrating immune cells are capable of secreting pro-inflammatory cytokines including tumour necrosing factor-α (TNFα) and interleukin-1β (IL-1β). In this study, we examine the potential of these cytokines to alter levels of MMPs and TIMPs in human mesangial cells. Methods: The T-HMC human mesangial cell line was cultured in RPMI 1640 containing 5% serum. Cells at confluency were serum starved for 24 h prior to exposure to TNF-α (0.1–100 ng/ml) or IL-1β (0.1–100 ng/ml) or a combination of both for 48 h. Activity of MMP-9 was examined by gelatin zymography and TIMP-1 expression was analysed by Western blotting. Results: TNF-α but not IL-1β resulted in a dose-dependent increase in the latent form of MMP-9 and a decrease in TIMP-1 production. Co-treatment with IL-1β had no effect on the induction of MMP-9 but increased the inhibition of TIMP-1 in the presence of TNF-α. Inhibition of PKC provided evidence of the importance of this pathway in mediating the TNF-α-induced suppression of TIMP-1. Activation of the ERK 1/2 MAPK mediated both the upregulation of MMP-9 and the inhibition of TIMP-1 following TNF-α treatment. p38 MAPK activation was also found to be involved in the TNF-α-stimulated MMP-9. Conclusion: The cytokine TNF-α causes different effects on human mesangial MMP-9 and TIMP-1 expression which are mediated through the TNF-RI, and the different signalling pathways of PKC, ERK 1/2 and p38 MAPK. This suggests an important role for pro-inflammatory cytokines in renal disease progression.

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Application of Antibody Array Technology in the Analysis of Urinary Cytokine Profiles in Patients with Chronic Kidney Disease

Cited by 55 publications

References 40 publications

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis

Increased Matrix Metalloproteinase 2 Activity in the Human Internal Mammary Artery Is Associated with Ageing, Hypertension, Diabetes and Kidney Dysfunction

TNF-Alpha and IL-1Beta-Mediated Regulation of MMP-9 and TIMP-1 in Human Glomerular Mesangial Cells

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