Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases

Abstract

The accumulation of extracellular matrix (ECM) within the kidney is an ultrastructural hallmark of diabetic nephropathy and is directly linked to a decline in renal function [1]. This increase of ECM can result from either increased synthesis and decreased degradative activity or both. Several studies have shown that high glucose concentration increases synthesis of ECM proteins in both mesangial and tubular epithelial cells [2]. However, more recently it has also Diabetologia (2002) Abstract Aims/hypothesis. Extracellular matrix accumulation is thought to be involved in the pathogenesis of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting, have not been fully explored. Furthermore, the effect of renoprotective therapies on matrix accumulation through these pathways has not been examined. We investigated the degradative pathway of type IV collagen and the effects of ACE inhibition in experimental diabetic nephropathy. Methods. Diabetes was induced in 16 rats by administrating streptozocin; 8 of the diabetic rats were allocated at random to receive the ACE inhibitor perindopril (2 mg/l) in their drinking water and 8 age and weight matched rats served as controls. Gene expression of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) was measured by RT-PCR and type IV collagen content by immunohistochemistry. MMP activities were determined by degradation of a radiolabelled substrate and by zymography.Results. Six months of diabetes was associated with a decrease in mRNA and enzymatic activity of MMP-9 (21 % and 51 % respectively, p < 0.05 vs control) and a 51 % increase in TIMP-1 mRNA (p < 0.05 vs control). By contrast, MMP-2 mRNA was increased but its activity decreased (43 % and 43 % respectively, p < 0.05 vs control). Total degradative capacity of kidney tissue from diabetic rats was also lower (Control: 48 7 %, Diabetic: 33 6 %, p < 0.05). Activation of latent MMPs with amino-phenylmercuric acetate increased matrix degradation by two-fold. However the relative decrease associated with experimental diabetes still remained. All diabetes-associated changes in MMP and TIMP mRNA and activities were attenuated by perindopril treatment in association with reduced type IV collagen accumulation. Conclusions/interpretation. These results indicate that the impairment of matrix degradation contributes to matrix accumulation in diabetic nephropathy and that the beneficial effects of ACE inhibition could in part be mediated by modulation of changes in matrix degradative pathways. [Diabetologia (2002) 45: 268±275]

Insulin-mediated activation of activator protein-1 through the mitogen-activated protein kinase pathway stimulates collagenase-1 gene transcription in the MES 13 mesangial cell line

“…This hypothesis may have a broader significance since AP-1 motifs are important for the expression of the genes encoding several matrix metalloproteinases other than collagenase (Vincenti 2001). These include both MMP-2 and MMP-9 whose glomerula expression, like that of collagenase, is also decreased in type I diabetes (Nakamura et al 1994, McLennan et al 2002. Although the synthesis of MMP-2 was widely considered, in contrast to collagenase and MMP-9, to be independent of AP-1 (Benbow & Brinckerhoff 1997, Westermarck & Kahari 1999, it has recently been shown that MMP-2 is regulated through a non-consensus AP-1 motif that binds members of the AP-1 transcription factor family (Bergman et al 2003).…”

“…Although in the streptozotocin rat model of type I diabetes, the glomerula expression of collagenase, MMP-2 and MMP-9 are all decreased (Nakamura et al 1994, McLennan et al 2002, the former MMP is associated with degradation of type 1 collagen whereas type 4 collagen is the principal collagen to accumulate in the glomerulus in diabetic nephropathy (Mauer 1994). Type 4 collagen is a substrate for MMP-2 and MMP-9 (Nagase & Woessner 1999, Brinckerhoff & Matrisian 2002.…”

“…This expansion of the mesangial matrix and the thickening of the glomerular basement membrane can be attributed to a stimulation of ECM protein synthesis and a decrease in ECM degradation, a secondary consequence of reduced MMP activity (Lenz et al 2000, Mason & Wahab 2003. In the streptozotocin rat model of type I diabetes, the expression of genes encoding three prominent MMPs, MMP-1 (collagenase-1; referred to henceforth as collagenase), MMP-2 and MMP-9 is decreased in the glomerulus (Nakamura et al 1994, McLennan et al 2002. The decrease in collagenase gene expression is reversed by insulin treatment (Nakamura et al 1994), but the effect of insulin treatment on MMP-2 and MMP-9 gene expression has not been explored.…”

Prevention and Regression of Chronic Kidney Disease and Hypertension

“…In contrast to gelatinase B (MMP-9), MMP-2 is not highly expressed in normal or diseased glomeruli (Urushihara et al, 2002). However, it has been shown that renal MMP-2 expression and activity are upregulated by ACE inhibitors in rats with diabetes (McLennan et al, 2002), (Sun et al, 2006). Moreover, Turkay et al reported that the ACE inhibitor enalapril also increased hepatic MMP-2 expression in rats with experimental hepatic fibrogenesis (Turkay et al, 2008), while Westermann et al showed that the ARB irbesartan increased MMP-2 activity in the hearts of mice with cardiomyopathy (Westermann et al, 2007), suggesting that the RAS plays a key role in regulation of MMP-2 expression in the kidney and other tissues.…”

Minocycline with Aspirin: An Approach to Attenuate Diabetic Nephropathy in Rats

“…Several studies have shown that high glucose concentration increases synthesis of ECM proteins in both mesangial and tubular epithelial cells. 7 Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidase that mediate the degradation or remodeling of the ECM. 8 The ECM is a multifunctional complex of proteins and proteoglycans assembled in a highly organized manner that contributes to the structural integrity of cells and tissue within an organ system.…”