Kinetics of connective tissue growth factor expression during experimentalproliferative glomerulonephritis

Connective tissue growth factor (CTGF) is a member of the CCN family of imm ediate early genes, which are involved in cell proliferation, migration, an d matrix production. Recently, CTGF was observed to be strongly upregulated in human proliferative and fibrogenic renal disease. By in situ hybridizat ion and reverse transcriptase-PCR, the expression of CTGF was investigated in experimental proliferative glomerulonephritis induced by injection of an ti-Thy-1.1 antibody in the rat. CTGF expression in cultured rat mesangial c ells and glomerular visceral epithelial cells (GVEC) was studied in respons e to transforming growth factor beta (TGF-beta), 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 increase d in extra-capillary and mesangial proliferative lesions and in areas of pe riglomerular fibrosis. Early glomerular CTGF overexpression in GVEC coincid ed with a striking upregulation of TGF-beta2 and to a lesser extent of TGF- beta3. Glomerular CTGF mRNA expression was maximal at day 7, in association with increased TGF-beta1 mRNA and protein expression. CTGF mRNA overexpres sion by parietal epithelial cells preceded the periglomerular appearance of alpha -smooth muscle actin-positive fibroblasts. In cultured mesangial cel ls, TGF-beta1, -beta2, and -beta3 transiently increased the CTGF/glyceralde hyde phosphate dehydrogenase mRNA ratio up to threefold versus control at 4 h. In GVEC, upregulation of CTGF mRNA by these TGF-beta 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 downstre am of TGF-beta, in this model of transient renal injury.