Do matrix metalloproteinases MMP-2 and MMP-9 (gelatinases) play a role in renal development, physiology and glomerular diseases?

Lelongt, Brigitte; Legallicier, B.; Piedagnel, Rémi; Ronco, Pierre

doi:10.1097/00041552-200101000-00002

Cited by 73 publications

(64 citation statements)

References 34 publications

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“…15,16 Hence, the increase in TIMP-1 and TIMP-2 protein expression was accompanied by downregulation of the expression and activity of MMP-2, MT1-MMP (involved in MMP-2 activation 39 ), and MMP-9. MMP-2 and MMP-9 are capable of digesting denatured and native collagen IV, 40,41 which is often produced in the damaged kidney, as we observed in HC-HC animals. The MMPs have a key role preserving the damaged kidney.…”

Section: Discussionsupporting

confidence: 55%

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

et al. 2005

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Abstract-Dyslipidemia often accompanies and accelerates renal disease, partly by promoting fibrosis. However, the mechanisms mediating this effect are unclear. We hypothesized that hypercholesterolemia modulates several interlinked pathways that promote deposition and blunt degradation of extracellular matrix, and that these could be manipulated by reversal of hypercholesterolemia. Fourteen pigs were fed a 16-week 2% high-cholesterol diet (HC-HC; nϭ7) or normal diet (nϭ7), whereas in 7 others, a 10-week HC was followed by a 6-week normal diet (HC-N). Renal endothelial function was assessed in vivo with electron-beam computed tomography, and renal tissue was then studied ex vivo using Western blot, real-time quantitative polymerase chain reaction, gelatin zymography, and immunostaining. HC-HC kidneys showed endothelial dysfunction, accompanied by increased intrarenal oxidative stress, inflammation, activation of the endothelin and transforming-growth factor-␤ systems, and decreased matrix metalloproteinase expression and activity. Accordingly, HC-HC kidneys showed increased collagen IV expression and fibrosis. A lipid-lowering dietary intervention reversed most of these changes. In conclusion, this study indicates that renal fibrosis in early atherosclerosis is a result of a simultaneous increase in extracellular matrix deposition and blunted matrix metalloproteinase-mediated degradation, overall promoting perivascular and tubulointerstitial fibrosis. Notably, many of these pathways may be reversible in hypercholesterolemia, and crucial targets could potentially be identified for early interventions to preserve the kidney. Key Words: kidney Ⅲ hypercholesterolemia Ⅲ fibrosis Ⅲ remodeling Ⅲ oxidative stress H ypercholesterolemia is a common cardiovascular risk factor. Approximately 50% of the middle-aged adult population has total cholesterol above desirable levels, 1 a strong, independent predictor of progression of atherosclerosis. 2 Dyslipidemia also often accompanies and aggravates early and advanced renal disease. 3,4 We have previously shown in a pig model that a 10-to 12-week diet-induced hypercholesterolemia, a risk factor for early atherosclerosis, elicited renal dysfunction, inflammation, and fibrosis, partly mediated by increased oxidative stress. [5][6][7][8] Increased oxidative stress may contribute to renal damage in hypercholesterolemia and atherosclerosis by virtue of augmented generation of reactive oxygen species (ROS) and oxidation of LDLs, 8 -12 which may induce endothelial dysfunction and activate redox-sensitive growth factors and cytokines. In addition, lipid accumulation or cellular damage can promote renal dysfunction, glomerular injury, and interstitial fibrosis. 13,14 A dynamic and complex process in which tissue growth is counterbalanced by degradation and removal preserves the normal structure of the kidney and may be partly modulated by endothelium-derived factors. Kidney disease and normal renal development are characterized by a high rate of extracellular matrix (ECM) turnover. Sev...

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Section: Discussionsupporting

confidence: 55%

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

et al. 2005

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“…We therefore next examined whether proteinases, in addition to proteinase inhibitors, directly participate in the regression process induced by Ang inhibition. MMP-2 and MMP-9 both are normally expressed in the glomerulus and thus have particular relevance to glomerular collagen remodeling (29,30). Downregulation of MMP has been associated with ECM accumulation and progression of renal diseases.…”

Section: Discussionmentioning

confidence: 99%

Regression of Glomerulosclerosis with High-Dose Angiotensin Inhibition Is Linked to Decreased Plasminogen Activator Inhibitor-1

Ma¹,

Nakamura²,

Aldigier³

et al. 2005

Journal of the American Society of Nephrology

138

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The potential and possible mechanisms for regression of existing glomerulosclerosis by angiotensin II type 1 receptor antagonist (AT1RA) and/or angiotensin I converting enzyme inhibitor (ACEI) were investigated. Adult male Sprague Dawley rats underwent 5/6 nephrectomy (Nx). Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into groups with equal biopsy sclerosis and treated for the next 4 wk until they were killed at 12 wk as follows: Control with no further treatment (CONT), high-dose AT1RA, high-dose ACEI, and varying AT1RA؉ACEI combinations. Hypertension and proteinuria induced by 5/6 Nx were significantly decreased by all treatments, except high-dose ACEI, which showed persistent proteinuria. High-dose AT1RA and ACEI markedly decreased progression of sclerosis, with ؊2.3% average decrease in sclerosis from biopsy to autopsy in AT1RA versus 194% increase in CONT (P < 0.0001). Glomerulosclerosis regressed, with less severe lesions at the time when the rats were killed than at biopsy in 62% of AT1RA-treated and 57% of ACEI-treated rats. In contrast, only 17 to 33% of rats in combination groups had regression. Alternatively, these data might be viewed as reflecting halting of progression, as some groups had higher BP and proteinuria. However, this potential confounding effect does not negate the effects to achieve regression of sclerosis in these rats. Regression was not explained by changes in mRNA of TGF-␤1 and matrix metalloproteinase-2 and -9 but was linked to decreased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. It is concluded that angiotensin inhibition mediates regression in part by effects on matrix modulation.

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“…That is, although MMP-2 expression and activity was significantly increased in damaged glomeruli of Ren2 rats and normalized after ramipril treatment, MMP-9 expression and activity was markedly suppressed in isolated glomeruli of Ren2 animals and unaffected by ACE inhibition. Alterations of renal MMP expression have been documented in a variety of kidney diseases (Lelongt et al, 2001). MMPs are proteases, and it is generally accepted that they contribute to matrix degradation with prevention of matrix accumulation (Nagase and Woessner, 1999;Lenz et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to membrane-bound membranetype MMPs, MMPs such as MMP-2 and MMP-9 are secreted in an inactive form and are subsequently activated extracellularly by other already activated MMPs or serine proteinases (Sternlicht and Werb, 2001;Snoek-van Beurden and Von den Hoff, 2005). In the kidney, MMP-2 and -9 are expressed in the glomerulus, and several reports indicate their importance in controlling ECM turnover in disease states (Lenz et al, 2000;Lelongt et al, 2001;Donnelly et al, 2003). Regulation of MMP activity is controlled at three levels: transcription, activation of the proenzyme, and inhibition by TIMPs.…”

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confidence: 99%

Expression and Response to Angiotensin-Converting Enzyme Inhibition of Matrix Metalloproteinases 2 and 9 in Renal Glomerular Damage in Young Transgenic Rats with Renin-Dependent Hypertension

Bolbrinker

Marković²,

Wehland³

et al. 2005

J Pharmacol Exp Ther

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Extracellular matrix expansion in the glomerular mesangium contributes to the development of glomerulosclerosis and chronic renal disease in arterial hypertension. Transforming growth factor-␤1 (TGF-␤1), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) are involved in this process. Conflicting data are reported on the effects of angiotensin II (Ang II) and the response to angiotensin-converting enzyme inhibition on MMPs and TIMPs in early stages of hypertensive glomerular damage. We therefore investigated the effects of Ang II-dependent hypertension on MMP-2, MMP-9, TIMP-1, and TIMP-2 in isolated glomeruli of 8-week-old homozygous male rats overexpressing the mouse Ren2 gene [TGR(mRen2)27]. At this age, systolic blood pressure was already significantly elevated in Ren2 compared with SpragueDawley (SD) rats (197 Ϯ 38 versus 125 Ϯ 16 mm Hg, p Ͻ 0.01). Ren2 exhibited renal damage as determined by increased urinary albumin excretion, focal glomerulosclerosis, mesangial matrix expansion, and ␣-smooth muscle actin deposition. Quantification of mRNA levels in isolated glomeruli by real-time polymerase chain reaction showed a significant increase of TGF-␤1, a 2.3-and a 2.6-fold increase of MMP-2 and TIMP-1 in Ren2 compared with SD (p Ͻ 0.01, respectively) and no strain differences for TIMP-2. In contrast, MMP-9 mRNA expression was markedly suppressed to 10% of control levels in Ren2 (p Ͻ 0.01). Early treatment with ramipril completely prevented renal damage in Ren2 and restored mRNA expression of TGF-␤1, MMP-2, and TIMP-1 to SD control levels. Interestingly, down-regulation of MMP-9 mRNA, protein, and activity was not affected by ramipril, indicating that the protective effect of this compound is not attributable to restoration of MMP-9 in the glomerulus.

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Do matrix metalloproteinases MMP-2 and MMP-9 (gelatinases) play a role in renal development, physiology and glomerular diseases?

Cited by 73 publications

References 34 publications

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

Regression of Glomerulosclerosis with High-Dose Angiotensin Inhibition Is Linked to Decreased Plasminogen Activator Inhibitor-1

Expression and Response to Angiotensin-Converting Enzyme Inhibition of Matrix Metalloproteinases 2 and 9 in Renal Glomerular Damage in Young Transgenic Rats with Renin-Dependent Hypertension

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