CCN3 is a novel endogenous PDGF-regulated inhibitor of glomerular cell proliferation

Abstract

CCN proteins affect cell proliferation, migration, attachment, and differentiation. We identified CCN3 as a suppressed gene following platelet-derived growth factor (PDGF)-BB or -DD stimulation in a cDNA-array analysis of mesangial cells. In vitro growth-arrested mesangial cells overexpressed and secreted CCN3, whereas the addition of the recombinant protein inhibited cell growth. Induction of mesangial cell proliferation by PDGF-BB or the specific PDGF beta-receptor ligand PDGF-DD led to downregulation of CCN3 mRNA, confirming the array study. Specific PDGF alpha-receptor ligands had no effect. CCN3 protein was found in arterial smooth muscle cells, the medullary interstitium, and occasional podocytes in the healthy rat kidney. Glomerular CCN3 was low prior to mesangial proliferation but increased as glomerular cell proliferation subsided during mesangioproliferative glomerulonephritis (GN). Inhibition of PDGF-B in mesangioproliferative disease led to overexpression of glomerular CCN3 mRNA. CCN3 localized mostly to podocytes in human glomeruli, but this expression varied widely in different human glomerulonephritides. Glomerular cell proliferation negatively correlated with CCN3 expression in necrotizing GN. Our study identifies CCN3 as an endogenous inhibitor of mesangial cell growth and a modulator of PDGF-induced mitogenesis.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…One such example is CCN3 (also known as nephroblastoma-overexpressed, NOV), which in the kidney appears to be an antagonist of PDGF-induced mesangial cell activation and proliferation (352,353).…”

A novel role of CCN3 in regulating endothelial inflammation

“…Recently, an intriguing study highlighted an important role of CCN3 in stem cell renewal (Gupta et al 2007). In the cardiovascular system, CCN3 expression has been demonstrated in fibroblasts, smooth muscle and endothelial cells (Kocialkowski et al 2001;Su et al 2001;van Roeyen et al 2008). In rat smooth muscle cells, CCN3 acts as an adhesion factor and is induced upon vascular injury (Ellis et al 2000;Su et al 2001).…”

The PDGF family in renal fibrosis

“…Several modes of fine tuning of PDGFR signaling were already mentioned earlier in this review, and most of them are probably valid for the kidney. In addition, we recently identified a PDGF-regulated endogenous downstream antagonist, nephroblastoma-overexpressed gene (NOV/CCN3), by a gene-array approach in human mesangial cells [60]. This factor is overexpressed in growtharrested mesangial cells and downregulated upon stimulation with PDGF-B or -D. Furthermore, in a model of mesangioproliferative glomerulonephritis, CCN3 expression is low prior to mesangial proliferation but increases as glomerular cell proliferation subsides [60].…”

“…This factor is overexpressed in growtharrested mesangial cells and downregulated upon stimulation with PDGF-B or -D. Furthermore, in a model of mesangioproliferative glomerulonephritis, CCN3 expression is low prior to mesangial proliferation but increases as glomerular cell proliferation subsides [60]. Recombinant CCN3 growth inhibited proliferation of human mesangial cells, and in human necrotizing glomerulonephritis, the glomerular cell proliferation correlated negatively with CCN3 expression [60]. We recently overexpressed CCN3 systemically in the early mesangiolytic phase of experimental mesangioproliferative glomerulonephritis in rats and identified a dual role of CCN3 with both proangiogenic and antimesangioproliferative effects, both of which serve to reconstitute normal glomerular architecture (unpublished data).…”

“…In addition, we recently identified a PDGF-regulated endogenous downstream antagonist, nephroblastoma-overexpressed gene (NOV/CCN3), by a gene-array approach in human mesangial cells [60]. This factor is overexpressed in growtharrested mesangial cells and downregulated upon stimulation with PDGF-B or -D. Furthermore, in a model of mesangioproliferative glomerulonephritis, CCN3 expression is low prior to mesangial proliferation but increases as glomerular cell proliferation subsides [60]. Recombinant CCN3 growth inhibited proliferation of human mesangial cells, and in human necrotizing glomerulonephritis, the glomerular cell proliferation correlated negatively with CCN3 expression [60].…”