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Frenay A.-R.S.,University of Groningen | Yu L.,University of Groningen | Yu L.,Harbin Medical University | van der Velde A.R.,University of Groningen | And 6 more authors.
American Journal of Physiology - Renal Physiology | Year: 2015

Galectin-3 activation is involved in the pathogenesis of renal damage and fibrogenesis. Limited data are available to suggest that galectin-3-targeted intervention is a potential therapeutic candidate for the prevention of chronic kidney disease. Homozygous TGR(mREN)27 (REN2) rats develop severe high blood pressure (BP) and hypertensive end-organ damage, including nephropathy and heart failure. Male REN2 rats were treated with N-acetyllactosamine [galectin-3 inhibitor (Gal3i)] for 6 wk; untreated REN2 and Sprague-Dawley rats served as controls. We measured cardiac function with echocardiogram and invasive hemodynamics before termination. BP and proteinuria were measured at baseline and at 3 and 6 wk. Plasma creatinine was determined at 6 wk. Renal damage was assessed for focal glomerular sclerosis, glomerular desmin expression, glomerular and interstitial macrophages, kidney injury molecule-1 expression, and α-smooth muscle actin expression. Inflammatory cytokines and extracellular matrix proteinases were quantified by quantitative real-time PCR. Systolic BP was higher in control REN2 rats, with no effect of Gal3i treatment. Plasma creatinine and proteinuria were significantly increased in control REN2 rats; Gal3i treatment reduced both. Renal damage (focal glomerular sclerosis, desmin, interstitial macrophages, kidney injury molecule-1, α-smooth muscle actin, collagen type I, and collagen type III) was also improved by Gal3i. All inflammatory markers (CD68, IL-68, galectin-3, and monocyte chemoattractant protein-1) were elevated in control REN2 rats and attenuated by Gal3i. Markers of extracellular matrix turnover were marginally altered in untreated REN2 rats compared with Sprague-Dawley rats. In conclusion, galectin-3 inhibition attenuated hypertensive nephropathy, as indicated by reduced proteinuria, improved renal function, and decreased renal damage. Drugs binding to galectin-3 may be therapeutic candidates for the prevention of chronic kidney disease. © 2015 the American Physiological Society. Source


Martinez-Martinez E.,Complutense University of Madrid | Miana M.,Complutense University of Madrid | Jurado-Lopez R.,Complutense University of Madrid | Rousseau E.,University of Lorraine | And 5 more authors.
PLoS ONE | Year: 2013

Background: The function of the Interleukin-33 (IL-33)/ST2 system has been mainly investigated on immunological aspects, but recent data suggest that this pathway plays also an important role in cardiovascular system and adipose tissue. Whereas IL-33 has been demonstrated to exert anti-inflammatory and protective effects, circulating soluble ST2 (sST2) has emerged as a prognostic biomarker in patients with myocardial infarction and heart failure. Furthermore, sST2 is increased in severe obesity, although its role in the pathogenesis of vascular remodeling associated with obesity is still not well defined. Methodology/Principal Findings: Male Wistar rats fed standard diet (Control) or high fat diet (HFD) for 6 weeks. Aortic tunica media from diet-induced obese animals showed hypertrophy and fibrosis. The IL-33/ST2 system was spontaneously expressed in the aorta from Wistar rats. Administration of HFD in animals did not modify IL-33 expression at the transcriptional level. By contrast, HFD group showed an increase in aortic soluble sST2 and a decrease in the transmembrane isoform (ST2L) levels, resulting in decreased protective pathway activity. Aortic sST2 mRNA levels were associated with parameters showing vascular hypertrophy and fibrosis. In vitro experiments showed that primary cultured vascular smooth muscle cells (VSMCs) spontaneously expressed the IL-33/ST2 system. VSMCs stimulated with sST2 showed an increase in collagen type I, fibronectin and profibrotic factors. Conclusions: This is the first study demonstrating a deleterious role for sST2 in the vascular remodeling associated with obesity. In addition, we demonstrated that sST2 may act not only as a decoy receptor by binding IL-33 and preventing ST2L, but also modulating ECM remodeling and turnover. Thus, sST2 could be a new therapeutic target to reduce vascular remodeling in the context of obesity. © 2013 Martínez- Martínez et al. Source


Martinez-Martinez E.,Complutense University of Madrid | Jurado-Lopez R.,Complutense University of Madrid | Valero-Munoz M.,Complutense University of Madrid | Bartolome M.V.,Complutense University of Madrid | And 6 more authors.
Journal of Hypertension | Year: 2014

Objective: Leptin acts as a cardiac profibrotic factor. However, the mechanisms underlying this effect are unclear. Therefore, we sought to elucidate the mediators involved in this process and the potential role of leptin in cardiac fibrosis associated with obesity. Methods: Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks. Results: HFD animals show cardiac hypertrophy, fibrosis and an increase in O2 - production as evaluated by dihydroethidium. Echocardiographic parameters of cardiac structure and systolic function were similar in both groups. Cardiac levels of leptin, collagen I, galectin-3 and transforming growth factor β (TGF-β) were higher in HFD than in controls. In cardiac myofibroblasts, leptin (10-100 ng/ml) increased O 2 -, collagen I, galectin-3, TGF-β and connective tissue growth factor production (CTGF). These effects were prevented by the presence of either melatonin (10-3 mmol/l) or the inhibitor of mTOR, rapamycin (10-4 mmol/l). Blockage of galectin-3 activity by N-acetyllactosamine (LacNac 10-3 mmol/l) reduced both collagen I and O2 - production induced by leptin. The p70S6 kinase activation/phosphorylation, the downstream mediator of mTOR, induced by leptin was not modified by melatonin. Leptin reduced the metalloproteinase (MMP) 2 activity and the presence of melatonin, rapamycin or LacNac were unable to prevent it. Conclusion: The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-b and CTGF through oxidative stress increased by activation of mTOR pathway. © 2014 Wolters Kluwer Health / Lippincott Williams & Wilkins. Source


Martinez-Martinez E.,Complutense University of Madrid | Miana M.,Cardiovascular Translational Research | Jurado-Lopez R.,Complutense University of Madrid | Bartolome M.V.,Complutense University of Madrid | And 4 more authors.
International Journal of Obesity | Year: 2014

Background/objectives:Extracellular matrix (ECM) participates in the vascular remodeling associated with obesity. We investigated the effects of leptin on the production of ECM components in primary cultured vascular smooth muscle cells (VSMCs) and whether leptin could be a mediator of obesity-induced vascular remodeling.Methods:The effects of leptin (100 ng ml-1) on ECM components and superoxide anion production (O 2.-) were evaluated in presence or absence of the antioxidant melatonin (10-3 mmol l-1) or the inhibitor of phosphatidylinositol 3′-kinase (PI3K), LY294002 (2 × 10-4 mmol l-1) in VSMCs from adult rats in order to explore the role of both oxidative stress and the participation of PI3K/Akt pathway in the effects of leptin. ECM components and O 2.-were quantified in the aortic media of male Wistar rats fed a high-fat diet (HFD; 33.5% fat), or a standard diet (CT; 3.5% fat) for 6 weeks.Results:In VSMCs, leptin enhanced gene and protein levels of collagen I, fibronectin, transforming growth factor (TGF)-β and connective tissue growth factor (CTGF) but did not change those of collagen III and galectin-3. Leptin also increased O 2.-And Akt phosphorylation in VSMCs. These effects were prevented by the presence of either melatonin or LY294002, except O 2.-production in the case of PI3K inhibition. The increase in body weight in HFD rats was accompanied by aorta thickening due to an increase in media area. The aortic fibrosis observed in HFD rats was associated with high levels of leptin, collagen type I, fibronectin, TGF-β, CTGF, phosphorylated Akt and O 2.-. Aortic leptin levels were positively correlated with total collagen, collagen I, TGF-β and CTGF levels. No differences were observed in the levels of collagen III, elastin or galectin-3 between both the groups.Conclusions:Leptin could participate in the vascular remodeling and stiffness associated with obesity by ECM production in VSMCs through the activation of oxidative stress-PI3K/Akt pathway and the production of the profibrotic factors TGF-β and CTGF. © 2014 Macmillan Publishers Limited All rights reserved. Source


Martinez-Martinez E.,Cardiovascular Translational Research | Cachofeiro V.,Complutense University of Madrid | Rousseau E.,Nancy University Hospital Center | Alvarez V.,Cardiovascular Translational Research | And 12 more authors.
Molecular and Cellular Endocrinology | Year: 2015

Interleukin-33 (IL-33) but not soluble ST2 (sST2) exerts anti-inflammatory and protective effects in several tissues. Aldosterone, a proinflammatory mediator which promotes adipogenesis, is elevated in obese patients. The aim of this study was to investigate the interactions between IL-33/ST2 system and Aldosterone in adipose tissue. Rats fed a high fat diet presented increased sST2 expression, diminished IL-33/sST2 ratio and enhanced levels of differentiation and inflammation in adipose tissue as compared to controls. A similar pattern was observed in adipose tissue from C57BL/6 Aldosterone-treated mice. In both animal models, Aldosterone was correlated with sST2. Treatment of 3T3-L1 adipocytes with IL-33 delayed adipocyte differentiation diminished lipid accumulation and decreased inflammation. Aldosterone decreased IL-33 and increased sST2 expressions in differentiated adipocytes. Aldosterone-induced adipocyte differentiation and inflammation were blocked by IL-33 treatment, but sST2 did not exert any effects. The crosstalk between IL-33/ST2 and Aldosterone could be relevant in the metabolic consequences of obesity. © 2015 Elsevier Ireland Ltd. Source

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