Renal expression of transforming growth factor-β inducible gene-h3 (βig-h3) in normal and diabetic rats

Gilbert, Richard E.; Wilkinson-Berka, Jennifer L.; Johnson, David W.; Cox, Alison; Soulis, T; Wu, Linlin; Kelly, Darren J.; Jerums, George; Pollock, Carol; Cooper, Mark E.

doi:10.1046/j.1523-1755.1998.00081.x

Cited by 87 publications

(81 citation statements)

References 63 publications

(51 reference statements)

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“…High dose omapatrilat not only reduced TGFβ1 expression but also decreased TGFβ1 bioactivity in a similar manner, as measured by the expression of the TGFβ1 dependent matrix protein βig-h3. This novel matrix protein has been previously shown to reflect the activity of TGFβ1 in both the human and experimental context [40,50], although the function of βig-h3 in renal physiology and pathogenic states remains unclear [22]. The lack of effect of perindopril or lowdose omapatrilat on TGFβ1 expression in these diabetic SHR, yet improvement in renal structural injury, emphasises that TGFβ1 alone cannot explain diabetes associated renal structural injury.…”

Section: Discussionmentioning

confidence: 98%

“…The sections were then fixed in 4% paraformaldehyde and treated with a progressive haematoxylin/eosin stain. Background hybridization was controlled for by the inclusion of a sense riboprobe in a method previously described [22,40]. Quantitation of the data was done on the renal cortex and corticomedullary junction from the autoradiography film for each probe.…”

Section: Gene Expression Of Transforming Growth Factor β1 (Tgfβ1) Andmentioning

confidence: 99%

“…Specifically, the recently described slit-pore protein nephrin, which has been postulated to modulate glomerular albumin permeability, was assessed [20]. In addition, expression of TGFβ, a prosclerotic cytokine implicated in diabetes-associated extracellular matrix accumulation [21] and the TGFβ dependent matrix protein, βig-h3 [22] were evaluated.…”

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confidence: 99%

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Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

et al. 2003

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Aims. Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Methods. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg −1 · day −1 ) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg −1 ·day −1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor β, β-inducible geneh3 and nephrin were also quantitated.Results. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFβ and βig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. Conclusion/Interpretation. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease. [Diabetologia (2003) 46:961-971]

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Section: Discussionmentioning

confidence: 98%

Section: Gene Expression Of Transforming Growth Factor β1 (Tgfβ1) Andmentioning

confidence: 99%

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Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

et al. 2003

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“…A number of studies have identified TGF-␤1 as a critical factor in kidney diseases such as glomerulosclerosis (8) and mesangioproliferative glomerulonephritis (9,10). TGF-␤1 stimulates the proliferation of mesangial cells and the production of extracellular matrix (11,12).…”

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confidence: 99%

Development of Gene Silencing Pyrrole-Imidazole Polyamide Targeting the TGF-β1 Promoter for Treatment of Progressive Renal Diseases

Matsuda¹,

Fukuda²,

Ueno³

et al. 2006

Journal of the American Society of Nephrology

102

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Pyrrole-imidazole (Py-Im) polyamides are nuclease-resistant novel compounds that inhibit gene expression by binding to the minor groove of DNA. A Py-Im polyamide that targets rat TGF-␤1 was designed as a gene-silencing agent for progressive renal diseases, and the distribution and the effects of this polyamide on renal injury were examined in Dahl-salt sensitive (Dahl-S) rats. For identification of transcription factor binding elements for activation of the rat TGF-␤1 gene, recombinant TGF-␤1 reporter plasmids were transfected into HEK-293 cells, and promoter activity was measured. Py-Im polyamide was designed to the activator protein-1 binding site of the rat TGF-␤1 promoter. This Py-Im polyamide showed strong, fast, and specific binding to the target DNA in gel mobility shift and Biacore assays. Py-Im polyamide significantly inhibited TGF-␤1 promoter activity and expression of TGF-␤1 mRNA and protein in rat mesangial cells. Intravenously administered fluorescein-labeled polyamide distributed to the kidney of rats. Py-Im polyamide significantly inhibited expression of TGF-␤1 mRNA and protein in the renal cortex of Dahl-S rats and reduced the increase in urinary protein and albumin in Dahl-S rats independent of changes in blood pressure. These results indicate that Py-Im polyamide that targets TGF-␤1 will be a novel gene-silencing agent for the TGF-␤1-associated diseases, including progressive renal diseases.

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“…Moreover, it inhibits the degradation of extracellular matrix by suppression of matrix metalloproteinases and induction of tissue inhibitors of these enzymes (20). A number of publications have identified TGF-␤1 as a critical factor in kidney diseases such as glomerulosclerosis (21) and mesangioproliferative glomerulonephritis (22). Furthermore, it has been shown that TGF-␤1 augments the accumulation of glomerular matrix through its induction of collagen type I (23).…”

mentioning

confidence: 99%

SPARC Regulates the Expression of Collagen Type I and Transforming Growth Factor-β1 in Mesangial Cells

Francki¹,

Bradshaw²,

Bassuk³

et al. 1999

Journal of Biological Chemistry

171

137

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The matricellular protein SPARC is expressed at high levels in cells that participate in tissue remodeling and is thought to regulate mesangial cell proliferation and extracellular matrix production in the kidney glomerulus in a rat model of glomerulonephritis (Pichler, R. H., Bassuk, J. A., Hugo, C., Reed, M. J., Eng, E., Gordon, K. L., Pippin, J., Alpers, C. E., Couser, W. G., Sage, E. H., and Johnson, R. J. (1997) Am. J. Pathol. 148, 1153-1167). A potential mechanism by which SPARC controls both cell cycle and matrix production has been attributed to its regulation of a pleiotropic growth factor. In this study we used primary mesangial cell cultures from wild-type mice and from mice with a targeted disruption of the SPARC gene. SPARC-null cells displayed diminished expression of collagen type I mRNA and protein, relative to wild-type cells, by the criteria of immunocytochemistry, immunoblotting, and the reverse transcription-polymerase chain reaction. The SPARC-null cells also showed significantly decreased steady-state levels of transforming growth factor-␤1 (TGF-␤1) mRNA and secreted TGF-␤1 protein. Addition of recombinant SPARC to SPARC-null cells restored the expression of collagen type I mRNA to 70% and TGF-␤1 mRNA to 100% of wildtype levels. We conclude that SPARC regulates the expression of collagen type I and TGF-␤1 in kidney mesangial cells. Since increased mitosis and matrix deposition by mesangial cells are characteristics of glomerulopathies, we propose that SPARC is one of the factors that maintains the balance between cell proliferation and matrix production in the glomerulus.

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Renal expression of transforming growth factor-β inducible gene-h3 (βig-h3) in normal and diabetic rats

Abstract: These findings support the hypothesis that biologically active TGF-beta plays a pathogenetic role in diabetic kidney disease and suggest that beta ig-h3 may be a useful index of TGF-beta1 bioactivity in the kidney.

Cited by 87 publications

References 63 publications

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

Development of Gene Silencing Pyrrole-Imidazole Polyamide Targeting the TGF-β1 Promoter for Treatment of Progressive Renal Diseases

SPARC Regulates the Expression of Collagen Type I and Transforming Growth Factor-β1 in Mesangial Cells

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