Renal fibrosis: Insights into pathogenesis and treatment

Nahas, A. Meguid El; Muchaneta-Kubara, E. C.; Essaway, M.; Söylemezoğlu, Oğuz

doi:10.1016/s1357-2725(96)00119-7

Cited by 84 publications

(54 citation statements)

References 41 publications

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“…In particular, secretion of galectin-3 is associated with activation of macrophages and fibroblasts, which leads to inflammation and fibrosis. Fibrosis is generally considered to be vital for tissue repair, including cardiac and renal disease [19][20][21][22]. It has been reported that galectin-3 is produced by macrophages and activated myofibroblasts in experimental models of cardiac [23,24], renal [25,26] and liver fibrosis [27].…”

Section: Discussionmentioning

confidence: 99%

The fibrosis marker galectin‐3 and outcome in the general population

Boer¹,

Veldhuisen²,

Gansevoort³

et al. 2011

Journal of Internal Medicine

343

291

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Abstract. de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJL, van der Harst P (University of Groningen). The fibrosis marker galectin-3 and outcome in the general population. J Intern Med 2012; 272: 55-64.Objective. Galectin-3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin-3 and cardiovascular (CV) risk factors and mortality in the general population.Design and subjects. This study included 7968 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, with a median follow-up of approximately 10 years. Plasma galectin-3 was measured in baseline samples.Main outcome measures. We investigated the relationships between galectin-3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all-cause, CV and cancer mortality.Results. The mean age of the population was 50 ± 13 years. Mean blood pressure was 129 ⁄ 74 mmHg, mean cholesterol was 5.7 ± 1.1 mmol L )1 and median galectin-3 was 10.9 ng mL )1 [interquartile range (IQR) 9.0-13.1]. Galectin-3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N-terminal pro-B-type natriuretic peptide (P < 0.0001). We observed a strong association between galectin-3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin-3 levels (11.0 ng mL )1 , IQR 9.1-13.4 vs. men (n = 3967) 10.7 ng mL )1 , IQR 8.9-12.8; P < 0.0001), and galectin-3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin-3 levels independently predicted all-cause mortality (hazard ratio per SD galectin-3 1.09, 95% CI 1.01-1.19; P = 0.036), but not CV and cancer mortality separately.Conclusions. Galectin-3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin-3 predicts all-cause mortality in the general population.

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Section: Discussionmentioning

confidence: 99%

The fibrosis marker galectin‐3 and outcome in the general population

Boer¹,

Veldhuisen²,

Gansevoort³

et al. 2011

Journal of Internal Medicine

343

291

View full text Add to dashboard Cite

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“…Considering that the magnitude of interstitial fibrosis strongly predicts the degree and progression to renal failure, 24,25 the antifibrotic effect of tamoxifen in this compartment may possibly be crucially relevant in attenuating the progression of renal disease. The effect of tamoxifen in ameliorating tubulointerstitial fibrosis seems directly related to a reduction in the synthesis of major ECM components, as demonstrated by the diminished production of collagen I, collagen III, and fibronectin in kidney tissue of tamoxifen-treated NAME rats.…”

Section: Discussionmentioning

confidence: 99%

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

Dellê

Rocha

Cavaglieri

et al. 2012

Journal of the American Society of Nephrology

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Tamoxifen, a selective estrogen receptor modulator, has antifibrotic properties; however, whether it can attenuate renal fibrosis is unknown. In this study, we tested the effects of tamoxifen in a model of hypertensive nephrosclerosis (chronic inhibition of nitric oxide synthesis with L-NAME). After 30 days, treated rats had significantly lower levels of albuminuria as well as lower histologic scores for glomerulosclerosis and interstitial fibrosis than untreated controls. Tamoxifen was renoprotective despite having no effect on the sustained, severe hypertension induced by L-NAME. Tamoxifen prevented the accumulation of extracellular matrix by decreasing the expression of collagen I, collagen III, and fibronectin mRNA and protein. These renoprotective effects associated with inhibition of TGF-b1 and plasminogen activator inhibitor-1, and with a significant reduction in a-smooth muscle actin-positive cells in the renal interstitium. Furthermore, tamoxifen abrogated IL-1b-and angiotensin-II-induced proliferation of fibroblasts from both kidney explants and from the NRK-49F cell line. Tamoxifen also inhibited the expression of extracellular matrix components and the production and release of TGF-b1 into the supernatant of these cells. In summary, tamoxifen exhibits antifibrotic effects in the L-NAME model of hypertensive nephrosclerosis, likely through the inhibition of TGF-b1, suggesting that it may have therapeutic use in CKD treatment.

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“…In experiments with AT-1a-receptor-deficient mice, diminished expression of MCP-1 led to markedly less interstitial fibrosis and preserved renal function in a mouse Amann, Tinzmann, and Angelkort model of anti-Gbm nephritis (28). Interstitial monocyte infiltration, extracellular matrix accumulation, and fibrosis of the kidney interstitium are also characteristic histological features of diabetic nephropathy in man (29). Monocytes move along a concentration gradient to the place with highest expression of MCP-1, which in the kidneys are the proximal tubular cells (30).…”

Section: Treatment Effectsmentioning

confidence: 97%

ACE Inhibitors Improve Diabetic Nephropathy Through Suppression of Renal MCP-1

2003

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OBJECTIVE -Chemokines play an important role in the pathogenesis of diabetic nephropathy. Angiotensin II induces several fibrogenic chemokines, namely monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-␤. The progression of diabetic nephropathy can be retarded by ACE inhibitors (ACEIs) in patients with type 1 and type 2 diabetes. We examined if blockade of the renin-angiotensin system lowered urinary levels of the chemokine MCP-1 and correlated urinary MCP-1 (uMCP-1) with parameters of renal function and glucose and lipid metabolism before and after 1 year of treatment with an ACE inhibitor.RESEARCH DESIGN AND METHODS -In 22 patients with type 2 diabetes and diabetic nephropathy in stages 3-5, treatment with the ACEI lisinopril was initiated. Before treatment and after 12 months of continuous therapy, proteinuria, creatinine clearance, uMCP-1 levels, BMI, HbA 1c , and serum cholesterol were assessed. CONCLUSIONS -Blockade of the renin-angiotensin system in type 2 diabetic patients with diabetic nephropathy reduces uMCP-1 levels and improves renal function. Because MCP-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of angiotensin II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal MCP-1. RESULTS Diabetes Care 26:2421-2425, 2003D iabetic nephropathy due to type 2 diabetes is becoming the single most important reason for endstage renal disease in the western world (1). Besides glomerular damage and glomerulosclerosis, diabetic nephropathy is characterized by aseptic tubulitis and tubulointerstitial fibrosis (2). Macrophages and macrophage products play an important pathogenic role in tubulointerstitial inflammatory and noninflammatory conditions and have been implicated as effector cells of tubulointerstitial damage in diabetic nephropathy (3,4). Increased numbers of glomerular and interstitial macrophages have been observed in rat models of experimental diabetes and in biopsies of patients with diabetic nephropathy (5). Monocytes are attracted to the place of organ damage by monocytespecific chemokines. Monocytes follow an endothelial-bound gradient of chemokine molecules and transmigrate from the vascular bed into the tissue at the point of the highest chemokine concentration (6). Therefore, systemic levels of chemokines do not reflect their local generation. A meaningful determination of chemokine expression can only be done in the anatomical compartment where chemokines are produced or in the near vicinity thereof. In renal diseases, this is either the kidney itself or urine.Monocyte chemoattractant protein-1 (MCP-1) is the strongest known chemotactic factor for monocytes and is upregulated in many renal diseases (7), including diabetic nephropathy (8). Renal MCP-1 expression is induced by elevated glucose levels, tubular reabsorbed protein, and probably advanced glycosylated end products (9). In diabetes, the tissue reninangi...

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Renal fibrosis: Insights into pathogenesis and treatment

Cited by 84 publications

References 41 publications

The fibrosis marker galectin‐3 and outcome in the general population

The fibrosis marker galectin‐3 and outcome in the general population

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

ACE Inhibitors Improve Diabetic Nephropathy Through Suppression of Renal MCP-1

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