ECM Gene Expression and Its Modulation by Insulin in Diabetic Rats

Fukui, Mitsumine; Nakamura, Tsukasa; Ebihara, Isao; Shirato, Isao; Tomino, Yasuhiko; Koide, Hikaru

doi:10.2337/diab.41.12.1520

Cited by 104 publications

(42 citation statements)

References 14 publications

(19 reference statements)

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“…Haneda et al [22], for example, reported that type IV collagen secreted from, and associated with, glomerular mesangial cells increased significantly when the cells were cultured in high concentrations of glucose. Moreover, the level of mRNA for type IV collagen was significantly increased in isolated glomeruli from diabetic rats [24]and in the cortical kidney from diabetic mice [25]. However, our recent studies in diabetic rats were unable to confirm increased glomerular or cortical mRNA expression for collagen IV by ISH or Northern blotting [unpubl.…”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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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“…Fukui et al [18] found an initial decrease in perlecan core protein mRNA expression in diabetic glomeruli, which normalized later. However, other studies have reported no change in perlecan mRNA expression in kidney tissues of diabetic rats [19] and mice [20].…”

Section: Discussionmentioning

confidence: 99%

Effects of advanced glycosylation endproducts on perlecan core protein of glomerular epithelium

Song

Lee

2004

Pediatr Nephrol

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Perlecan is one of major heparan sulfate proteoglycans in the glomerular basement membrane and is reduced in the renal parenchyma of diabetic patients and animals with proteinuria. To examine the effects of glucose and advanced glycosylated end-products (AGE) on perlecan, we cultured rat glomerular epithelial cells (GEpC) on AGE- or bovine serum albumin (BSA)-coated plates under normal (NG, 5 mM) and high-glucose (HG, 30 mM) conditions and measured the change in perlecan core protein production by a sandwich ELISA and northern blot analysis. We observed significant decreases of perlecan core protein under HG conditions at 1 week incubation, specifically on the AGE-coated compared with the BSA-coated surface, by 22.2% and 4.7%, respectively. The expression of mRNA for perlecan promoter was decreased under HG conditions on AGE-coated surfaces by 19.7% at 2 days and 61.1% at 1 week. Even under NG condition, the expression of mRNA was reduced by 30% at 1 week if GEpC were grown on an AGE-coated surface. In conclusion, HG and AGE have an additive effect in reducing the production of perlecan core protein by GEpC in vitro. AGE had a greater effect than HG, implying that the inhibition of AGE formation may be more effective than short-term glucose control in the prevention of diabetic proteinuria.

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“…Similar results have been obtained in experimental animals. Two independent studies demonstrated increased glomerular mRNA levels of collagen IV ~1 chain, and laminin B1 and B2 chain in kidneys of diabetic rats [9,18]. These changes which precede the basement membrane thickening could be prevented by normalization of blood glucose by insulin treatment.…”

mentioning

confidence: 82%

Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy

Olgemöller

Schleicher

1993

Clin Investig

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Diabetic late complications are characterized by morphological and biochemical alterations of the extracellular matrix. In particular, longstanding diabetes causes quantitative and qualitative changes in basement membrane structure of retinal and renal capilleries. Immunohistochemical investigations of diabetic kidneys with diffuse glomerulosclerosis show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial matrix and glomerular basement membrane as well. In nodular glomerulosclerosis normal basement membrane components are decreased or absent while the occurrence of collagen type III in this stage has been interpreted as an irreversible alteration of the glomerular structure. These changes seem to be the underlying cause for the alterations in renal functions like persistent albuminuria and proteinuria. Increased intra-and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are reports on possible genetic defects causing increased susceptibility to develop diabetic nephropathy. Recent results, however, focuse on the role of glucose-induced cytokine secretion as mediator for altered metabolism of glomerular matrix proteins. In vitro studies with cultured kidney cells have shown that the glucoseinduced dysregulation of the basement membrane synthesis may be mediated by a glucose dependent activation of protein kinase C. Alternatively or synergistically, the formation of AGE products formed after prolonged exposure of matrix proteins to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of cxtracellular matrix proteins. Studies in experimental animals confirm the diabetes induced dysregulation of the synthesis of extracellular matrix components on the molecular level.Abbreviations: HSPG=heparan sulfate proteoglycan; GBM= glomerular basement membrane; ECM=extracellular matrix; AGE = advanced glucosylation end products; TNF = tumor necrosis factor; bFGF=basic fibroblast growth factor

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ECM Gene Expression and Its Modulation by Insulin in Diabetic Rats

Cited by 104 publications

References 14 publications

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

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

Effects of advanced glycosylation endproducts on perlecan core protein of glomerular epithelium

Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy

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