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CCN3, a Key Matricellular Protein, Distinctly Inhibits TGFβ1-mediated Smad1/5/8 Signalling in Human Podocyte Culture

CCN3, a Key Matricellular Protein, Distinctly Inhibits TGFβ1-mediated Smad1/5/8 Signalling in Human Podocyte Culture

Tarunkumar Hemraj Madne, Mark Edward Carl Dockrell

Cell Mol Biol (Noisy-le-grand). 2018 Feb 28;64(3):5-10.

PMID: 29506624

Abstract:

Growth factors like TGFβ and CTGF (CCN2) plays a vital role in various cellular functions. TGFβ and CTGF are overexpressed in renal fibrosis. CTGF act as profibrotic stimuli to TGFβ. CCN3 is a member of CCN family which also comprises CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3). CCN3 has been shown to antagonise CTGF. In this study, we investigated the role of CCN3 in TGFβ1-mediated signalling in human podocytes culture. This study describes the novel function of CCN3 in regulation of TGFβ1 mediated non-canonical Smad signalling in human podocytes culture. Experiments were conducted on conditionally immortalised human podocytes incubated with TGFβ1 (1.25ng/ml and 2.5ng/ml) and CCN3 (360ng/ml). Western blot study was performed to study signalling proteins. RT-PCR was performed to study alternative splicing of Fibronectin (Fn). Real time PCR was performed to look for gene expression of Fn and collagen IV and collagen I. TGFβ1 induced the Smad1/5/8, Smad3 and p38 phosphorylation and CCN3 downregulated the TGFβ1 induced Smad1/5/8 phosphorylation and did not affect Smad3 and p38 phosphorylation. In addition to this CCN3 induced alternative splicing of Extra domain A Fibronectin (EDA+Fn). CCN3 also induced collagen IV, Collagen I and Fn gene expression. This is the first evidence of downregulation of TGFβ-mediated activation of a Smad1/5/8 signalling pathway by CCN3 in human podocytes and in any cell type. Targeting CCN3-mediated events could provide exciting outcomes in the understanding of molecular mechanism of fibrosis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413773	WISP-3 human			Price

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