Metalloproteinases in the Pathogenesis of Diabetic Nephropathy

Suzuki, Daisuke

doi:10.1159/000045156

Cited by 18 publications

(12 citation statements)

References 61 publications

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“…In particular, transforming growth factor-b (TGF-b), a prosclerotic growth factor, that has been consistently implicated in the ECM accumulation of diabetic nephropathy [27] acts by inhibiting matrix degradation as well as by stimulating its synthesis [28]. Indeed, our findings that MMP-2 and TIMP-1 gene expression were increased, while MMP-9 mRNA was decreased, were consistent with the described actions of TGF-b [25,26]. Furthermore, perindopril altered the changes in MMP-2 and TIMP-1 consistent with a previously reported diminution in the overexpression of TGF-b with ACE inhibition [7].…”

Section: Discussionsupporting

confidence: 86%

“…Gene expression of the type IV collagenases, MMP-2 and MMP-9 were affected in different ways by the diabetic state, with increased gene expression of MMP-2 and reduced expression of MMP-9. The differential regulation of the components of the matrix degradative pathways has been previously documented [24,25] and could be influenced by a range of factors which are altered in the diabetic milieu [26]. In particular, transforming growth factor-b (TGF-b), a prosclerotic growth factor, that has been consistently implicated in the ECM accumulation of diabetic nephropathy [27] acts by inhibiting matrix degradation as well as by stimulating its synthesis [28].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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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]

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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“…Although increased levels of ECM TIMP and low levels of MMP production could easily explain ECM expansion in DN, other possibilities are equally logical. Thus, low production of MMPs together with reduced ECM and TIMPs could also result in ECM expansion [33]. Moreover, glycosylation of renal ECM components [34, 35]could impair their degradation, leading to ECM accumulation.…”

Section: Discussionmentioning

confidence: 99%

Renal in situ Hybridization Studies of Extracellular Matrix Related Molecules in Type 1 Diabetes mellitus

Suzuki

Yagame

Kim

et al. 2002

Nephron

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Background/Aim: Progressive expansion of mesangial matrix and glomerular basement membrane thickening represent alterations in the balance between synthesis and degradation of glomerular extracellular matrix (ECM) protein and are hallmarks of diabetic nephropathy. In order to elucidate the basis for this imbalance between the synthesis and the degradation of ECM in renal tissues from patients of type 1 diabetes mellitus (type 1D) with diabetic nephropathy (DN), we examined the expression of α1 chain of type IV collagen (IV-C), matrix metalloproteinase-2 and -3 (MMP-2, MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and β-actin mRNA using a high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. Methods: Patients were divided into two groups based on both of degree of mesangial expansion using electron microscopic point counting morphometric methods and duration of type 1D: 7 ‘fast-track’ patients were selected for their very rapid development of DN structural changes and 8 ‘slow-track’ patients for their very slow development of DN structural changes. Seven normal human kidney (NHK) tissues were used as controls. Results: Positive cells for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman’s capsule. The percentage of glomerular cells positive for IV-C, MMP-2 and MMP-3 mRNA was significantly greater in the ‘slow-track’ vs. ‘fast-track’ patients. No significant differences in percentage positive cells was seen for β-actin mRNA. Furthermore, to elucidate the total number of positive cells per glomerulus for each mRNA, we estimated total cell number of glomerulus using morphometric techniques on light microscopy tissues. The total cell number per glomerulus was significantly greater in ‘fast-track’ than that in ‘slow-track’ patients and NHK. The total number of positive cells per glomerulus for MMP-2 in NHK was significantly greater than that in ‘slow-track’ and ‘fast-track’ patients. Conclusion: Thus, IV-C, MMP-2, MMP-3 and TIMP-1 mRNA are expressed in resident glomerular cells in renal tissues from NHK and type 1D. Glomerular alterations in these in situ mRNA expressions sufficient to explain ECM accumulation and DN risk were not uncovered. These largely negative results could be due to methodologic quantitative imprecision or could indicate that post-translational differences account for ECM imbalance in DN. However, these studies make it clear that unraveling the nature of the ECM production/removal imbalance in DN will require careful consideration of alterations in glomerular cell number.

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“…Alterations of such balance in renal disease may lead to a gradual augmentation of glomeruli and/or tubulointerstitium [11, 12, 13]. An important determinant of the net accumulation or breakdown of the ECM is the tightly regulated interplay between matrix metalloproteinases (MMPs) and their inhibitors [14].…”

Section: Introductionmentioning

confidence: 99%

Decreased Matrix Metalloproteinase Activity in the Kidneys of Hereditary Nephrotic Mice (ICGN Strain)

Uchio

Manabe

Tamura

et al. 2000

Nephron

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Abnormalities of extracellular matrix (ECM) metabolism, i.e., overproduction and/or inhibition of ECM breakdown, may contribute to progression of fibrotic degeneration in the kidney. Earlier studies revealed that major ECM components, type I, III, and IV collagens, etc., were accumulated in glomeruli and tubulointerstitium in kidneys of Institute of Cancer Research (ICR) derived glomerulonephritis (ICGN) mice which are a novel inbred strain of mice with a hereditary nephrotic syndrome of unknown etiology and are considered to be a good model of human idiopathic nephrotic syndrome. In the present study, we compared the activities of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components, in the kidneys of aged ICGN mice and age-matched ICR mice as normal controls. We biochemically measured interstitial collagenase (MMP-1), gelatinase (MMP-2 and MMP-9), and stromelysin (MMP-3) activities in the kidney tissues. Lower activities of MMP-1 and MMP-2 and MMP-9 were demonstrated in the kidneys of ICGN mice as compared with those of ICR mice, but there were no significant differences in the MMP-3 activities between these strains. These results show that decreased MMP activities cause abnormal accumulation of ECM in ICGN mouse kidneys.

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Metalloproteinases in the Pathogenesis of Diabetic Nephropathy

Cited by 18 publications

References 61 publications

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

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

Renal in situ Hybridization Studies of Extracellular Matrix Related Molecules in Type 1 Diabetes mellitus

Decreased Matrix Metalloproteinase Activity in the Kidneys of Hereditary Nephrotic Mice (ICGN Strain)

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