Expression patterns of connective tissue growth factor and of TGF-β isoforms during glomerular injury recapitulate glomerulogenesis

2010 ◽  
Vol 299 (3) ◽  
pp. F545-F558 ◽  
Author(s):  
Yasuhiko Ito ◽  
Roel Goldschmeding ◽  
Hirotake Kasuga ◽  
Nike Claessen ◽  
Masahiro Nakayama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Expression Patterns ◽  
Tissue Growth ◽  
Glomerular Injury

Transforming growth factor (TGF)-β1, -β2, and -β3 are involved in control of wound repair and development of fibrosis. Connective tissue growth factor (CTGF) expression is stimulated by all TGF-β isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGF-β1 or to facilitate interaction of TGF-β1 with its receptor, but its interactions with TGF-β isoforms in nonpathological conditions are unexplored so far. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGF-β, we compared expression patterns of CTGF and TGF-β isoforms in rat and human glomerulogenesis and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the comma- and S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGF-β1, -β2, and -β3 protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGF-β2 and -β3 protein, and in the absence of TGF-β1, CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGF-β1 and CTGF were again coexpressed, often with TGF-β2 and -β3, in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy (IgA NP). Coordinated expression of TGF-β isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGF-β1 and CTGF is associated with development of severe glomerulonephritis and glomerulosclerosis.

Connective tissue growth factor antagonizes transforming growth factor-β1/Smad signalling in renal mesangial cells

2011 ◽  
Vol 441 (1) ◽  
pp. 499-510 ◽  
Author(s):  
Helen C. O'Donovan ◽  
Fionnuala Hickey ◽  
Derek P. Brazil ◽  
David H. Kavanagh ◽  
Noelynn Oliver ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Transcriptional Responses ◽  
Cell Contractility ◽  
Tgf Β1

The critical involvement of TGF-β1 (transforming growth factor-β1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-β1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-β1 and its physiological significance. CTGF was determined to bind directly to the TβRIII (TGF-β type III receptor) and antagonize TGF-β1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-β1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-β1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-β1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF. Knockdown of TβRIII restored TGF-β1-mediated Smad signalling and cell contractility, suggesting that TβRIII is key for CTGF-mediated regulation of TGF-β1. Comparison of gene expression profiles from CTGF/TGF-β1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-β1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.

Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

2010 ◽  
Vol 298 (3) ◽  
pp. F796-F806 ◽  
Author(s):  
Sven Kroening ◽  
Emily Neubauer ◽  
Bernd Wullich ◽  
Jan Aten ◽  
Margarete Goppelt-Struebe
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Primary Cultures ◽  
Tissue Growth ◽  
Tubular Epithelial Cells ◽  
Mesenchymal Phenotype

Tubular epithelial cells secrete connective tissue growth factor (CTGF, CCN2), which contributes to tubulointerstitial fibrosis. However, the molecular regulation of CTGF in human primary tubular epithelial cells (hPTECs) is not well defined. Therefore, CTGF expression was characterized in hPTECs isolated from healthy parts of tumor nephrectomies, with special emphasis on the regulation by transforming growth factor-β (TGF-β) and hypoxia, essential factors in the development of fibrosis. CTGF synthesis was strongly dependent on cell density. High CTGF levels were detected in sparse cells, whereas CTGF expression was reduced in confluent cells. Concomitantly, stimulation of CTGF by TGF-β or the histone deacetylase inhibitor trichostatin was prevented in dense cells. Exposure of hPTECs to low oxygen tension (1% O2) or the hypoxia mimetic dimethyl-oxalylglycine for 24 h reduced CTGF gene expression in most of the 17 preparations analyzed. Preincubation of the cells under hypoxic conditions significantly reduced TGF-β-mediated upregulation of CTGF. In line with these data, CTGF mRNA was only induced in interstitial cells, but not in tubular cells in kidneys of mice exposed to hypoxia. Longer exposure to hypoxia or TGF-β (up to 72 h) did not induce hPTECs to adopt a mesenchymal phenotype characterized by upregulation of α-smooth muscle actin, downregulation of E-cadherin, or increased sensitivity of the cells in terms of CTGF expression. Sensitivity was restored by inhibition of DNA methylation. Taken together, our data provide evidence that exposure to hypoxia decreased CTGF gene expression. Furthermore, hypoxia per se was not sufficient to induce a mesenchymal phenotype in primary tubular epithelial cells.

scholarly journals Kinetics of Connective Tissue Growth Factor Expression during Experimental Proliferative Glomerulonephritis

2001 ◽  
Vol 12 (3) ◽  
pp. 472-484
Author(s):  
YASUHIKO ITO ◽  
ROEL GOLDSCHMEDING ◽  
RICHARD J. BENDE ◽  
NIKE CLAESSEN ◽  
M. ANWAR CHAND ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Connective Tissue ◽  
Mrna Expression ◽  
Connective Tissue Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Proliferative Glomerulonephritis ◽  
Kinetics Of ◽  
Tgf Β1

Abstract. Connective tissue growth factor (CTGF) is a member of the CCN family of immediate early genes, which are involved in cell proliferation, migration, and matrix production. Recently, CTGF was observed to be strongly upregulated in human proliferative and fibrogenic renal disease. By in situ hybridization and reverse transcriptase-PCR, the expression of CTGF was investigated in experimental proliferative glomerulonephritis induced by injection of anti—Thy-1.1 antibody in the rat. CTGF expression in cultured rat mesangial cells and glomerular visceral epithelial cells (GVEC) was studied in response to transforming growth factor β (TGF-β), an essential pathogenetic factor in this model. In normal rat kidneys, only some GVEC expressed CTGF mRNA. In anti—Thy-1.1 nephritis, CTGF mRNA expression was strongly increased in extracapillary and mesangial proliferative lesions and in areas of periglomerular fibrosis. Early glomerular CTGF overexpression in GVEC coincided with a striking upregulation of TGF-β2 and to a lesser extent of TGF-β3. Glomerular CTGF mRNA expression was maximal at day 7, in association with increased TGF-β1 mRNA and protein expression. CTGF mRNA overexpression by parietal epithelial cells preceded the periglomerular appearance of α-smooth muscle actin—positive fibroblasts. In cultured mesangial cells, TGF-β1, -β2, and -β3 transiently increased the CTGF/glyceraldehyde phosphate dehydrogenase mRNA ratio up to threefold versus control at 4 h. In GVEC, upregulation of CTGF mRNA by these TGF-β isoforms was more sustained, being 8- to 16-fold versus control at 24 h. The kinetics of CTGF expression strongly suggest a role in glomerular repair, possibly downstream of TGF-β, in this model of transient renal injury.

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