Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease

Border, Wayne A.; Noble, Nancy A.; Yamamoto, Tatsuo; Harper, John R.; Yamaguchi, Yu; Pierschbacher, Michael D.; Ruoslahti, Erkki

doi:10.1038/360361a0

Cited by 946 publications

(554 citation statements)

References 16 publications

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“…Thus, further studies are needed to explore the role of versican in diabetic nephropathy and other glomerular disorders. Our finding of a downregulation of the decorin core protein at D40 is consistent with the notion that this protein binds and neutralises extracellular TGF-β, thus antagonising the prosclerotic effect of this cytokine [45,46]. The biological functions of fibromodulin are largely unknown; however, fibromodulin also binds to active TGF-β [47].…”

Section: Discussionsupporting

confidence: 88%

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

et al. 2006

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Aims/hypothesis Despite the fact that diabetic nephropathy is an increasingly common disorder that may lead to uraemia, the underlying mechanisms are still poorly understood and there is no specific therapy. To clarify whether long-term diabetes alters glomerular size-or charge-selectivity or both, we studied non-obese diabetic mice for up to 40 weeks. Materials and methods During the study period, spot urine was collected and blood pressure measured. At weeks 10 and 40, the right kidney was isolated and perfused at 8°C to inhibit tubular function, allowing for analysis of glomerular selectivity with albumin and Ficoll clearance. The left kidney was removed for further investigation using electron microscopy and molecular biology. Real-time PCR with low-density arrays was done to evaluate renal cortex mRNA expression of proteoglycans and other components in the glomerular barrier. After 40 weeks of diabetes, kidneys showed morphological changes typical of diabetic complications. Results At 40 weeks, the fractional clearance for negatively charged albumin was three times higher in the diabetic animals (0.0160) than in controls (0.0051, p<0.001), while fractional clearance for neutral Ficoll 35.5 Å with a Stokes Einstein radius similar to that of albumin was unaffected. In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes. Conclusions/interpretation We conclude that glomerular charge-but not size-selectivity was impaired in the diabetic animals with proteinuria. Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes.

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Section: Discussionsupporting

confidence: 88%

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

et al. 2006

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“…25,[28][29][30] Decorin has the ability to inhibit TGF-b by forming an inactive complex. 4,31,32 Additionally, it has also been shown that decorin inhibits TGF-b mRNA transcription and TGF-b protein synthesis. 13,33 However, these functions appear to be highly cell-type specific.…”

Section: Discussionmentioning

confidence: 99%

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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Given the failure of conventional treatments for glioblastoma, gene therapy has gained interest considerable in recent years. Gliomas are associated with a state of immunosuppression, which appears to be partially mediated by an increase in secretion of transforming growth factor-b (TGF-b) from glioma cells. Decorin, a small proteoglycan which can bind to and inactivate TGF-b, has been successfully used as an antitumor strategy on stably transfected tumor cells and has been shown to cause growth suppression in neoplastic cells of various histological origins. In this paper, we investigated the use of gene therapy to deliver the decorin transgene in a site-specific manner in an experimental model of intracranial gliomas. Our aim was to inhibit the glioma-associated immunosuppressive state, and prolong the survival of tumor-bearing rats.We studied the effects of decorin gene transfer in the rat CNS-1 glioma model. To assess the effect of ectopic expression of decorin on glioma progression in vivo, stably transfected CNS-1 cells expressing decorin were implanted into the brain parenchyma of syngeneic Lewis rats. The rats implanted with CNS-1 cells expressing decorin survived significantly longer than those in the control groups which received CNS-1 cells that did not express decorin (Po.0001). We then investigated whether the survival observed with decorin expressing cells could be mimicked in vivo, using recombinant adenoviruses (RAds) expressing the decorin gene under the control of two different promoters: the human immediate-early cytomegalovirus (h-IE-CMV) and the glial fibrillary acidic protein (GFAP). In vivo results showed that administration of RAd expressing the human decorin under the control of h-IE-CMV promoter has a small, but significant effect in prolonging the survival of experimental tumor bearing rats (Po.0001). Our data indicate that ectopic decorin expression has the potential to slow glioma progression in vivo. Our results also indicate that expression of decorin has to be present in all cells which constitute the intracranial tumor mass for the inhibition of tumor growth and prolongation of the life expectancy of tumor-bearing rats to be effective.

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“…Many investigators have focused on TGF-β as a target for therapeutic intervention in experimental renal disease in rats [44][45][46][47][48] (Table 1). Much as it has been proposed that several molecules are involved in the autoregulation of TGF-β in vivo, these particular molecules have been used as targets in renal fibrosis.…”

Section: Transforming Growth Factor-betamentioning

confidence: 99%

“…Decorin in its turn is inactivated by the actions of several MMPs that can cleave it into fragments, liberating TGF-β from the ECM [50]. Intravenous application of decorin in experimental glomerulonephritis prevented TGF-β-mediated matrix accumulation [46]. Another example of an autoregulatory mechanism is the interaction between TGF-β and PAI-1.…”

Section: Transforming Growth Factor-betamentioning

confidence: 99%

ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor-beta, platelet-derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large-scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention.

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Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease

Cited by 946 publications

References 16 publications

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

ECM homeostasis in renal diseases: a genomic approach

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