CCN3 is a novel endogenous PDGF-regulated inhibitor of glomerular cell proliferation.
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.
van Roeyen
C R C
CR
Department of Nephrology, RWTH Aachen University, Pauwelsstrasse 30, D-52057 Aachen, Germany.
Eitner
F
F
Scholl
T
T
Boor
P
P
Kunter
U
U
Planque
N
N
Gröne
H-J
HJ
Bleau
A M
AM
Perbal
B
B
Ostendorf
T
T
Floege
J
J
D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology*; D055514:Nephroblastoma Overexpressed Protein; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050199:Podocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000819:agonists / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000819:agonists / Q000378:metabolism
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; C526319:CCN3 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D055514:Nephroblastoma Overexpressed Protein; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D055513:Connective Tissue Growth Factor; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta