title: Connective tissue growth factor antagonizes transforming growth factor-β1/Smad signalling in renal mesangial cells.
abstract: 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.
authors.affiliation: University College Dublin School of Biomolecular and Biomedical Science, Belfield, Dublin 4, Republic of Ireland.
authors.forename: Helen C
authors.initials: HC
authors.lastname: O'Donovan
authors.forename: Fionnuala
authors.initials: F
authors.lastname: Hickey
authors.forename: Derek P
authors.initials: DP
authors.lastname: Brazil
authors.forename: David H
authors.initials: DH
authors.lastname: Kavanagh
authors.forename: Noelynn
authors.initials: N
authors.lastname: Oliver
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: John
authors.initials: J
authors.lastname: Crean
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C071736:betaglycan