Connective tissue growth factor participates in scar formation of crescentic glomerulonephritis

Abstract

Glomerular crescents are a major determinant of progression in various renal diseases. Some types of growth factors are known to be involved in the evolution of crescents and the subsequent scar formation. Although glomerular parietal epithelial cells (PECs) are the major component of cellular crescents, the influence of growth factors on PECs is unknown. We performed immunohistochemical studies and in situ hybridization to examine alterations in connective tissue growth factor (CTGF) expression and to identify CTGF-synthesizing cells in crescents in the crescentic glomerulonephritis model of Wistar Kyoto rats. In addition, we examined the roles of fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta, and CTGF in cell proliferation and matrix synthesis in an established rat PEC cell line (PEC line). In an acute phase of rat crescentic glomerulonephritis, a major component of the crescents were macrophages, which did not express CTGF mRNA. However, in the advanced phase, crescents strongly expressed CTGF mRNA and the epithelial marker pan-cadherin but did not express the macrophage marker ED1, suggesting that PECs synthesized the CTGF. In the PEC line, FGF-2 predominantly promoted [(3)H]thymidine incorporation compared with PDGF-BB. Both TGF-beta and PDGF-BB strongly stimulated extracellular matrix synthesis in association with up-regulation of endogenous CTGF, but TGF-beta showed a predominant role. FGF-2 had a minor effect on it. In addition, blockade of endogenous CTGF using an antisense oligodeoxynucleotide significantly attenuated both TGF-beta- and PDGF-BB-induced extracellular matrix synthesis. These results suggest that several growth factors promote cell proliferation and matrix production in PECs. CTGF-mediated matrix production via the TGF-beta or PDGF-BB pathway in PECs may, in part, play a role in the progression of scar formation in crescents.