Osteopontin overproduction is associated with progression of glomerular fibrosis in a rat model of anti-glomerular basement membrane glomerulonephritis.
BACKGROUND
Glomerular fibrosis is the common end result of glomerulonephritis (GN) regardless of etiology. In our rat model for anti-glomerular basement membrane GN, severe fibrosis follows glomerular inflammation. We investigated the association between expression of extracellular matrix (ECM) proteins and progression of glomerular fibrosis.


METHODS
Expression of ECM genes in glomeruli was determined at RNA and protein levels. Immunofluorescence was applied to identify cell sources for the molecules.


RESULTS
DNA microarray for ECM genes, quantitative RT-PCR and Western blot revealed significant upregulation of osteopontin (OPN), a multifunctional molecule, in the glomeruli only after onset of glomerular fibrosis. Two-dimensional electrophoresis showed that the expressed OPN was in three major isoforms. Immunofluorescence showed that fibrotic tissues in glomeruli accumulated massive deposits of extracellular OPN. Both in vivo and in vitro experiments showed that a novel population of multinucleated α-smooth muscle actin(+)CD90(-) myofibroblast-like cells, which surrounded fibrotic tissue, was the main source of OPN during progression of fibrosis. Since senescence-associated β-galactosidase activity was detected in those cells both in vitro and in vivo, these cells probably were terminally differentiated senescent myofibroblasts.


CONCLUSIONS
OPN has been implicated in fibrosis in several organs. Our results suggest potential roles of OPN and its main source, the senescent myofibroblasts, in glomerular fibrosis.
Merszei
Justin
J
Wu
Jean
J
Torres
Lisa
L
Hicks
John M
JM
Bartkowiak
Todd
T
Tan
Filemon
F
Lou
Ya-Huan
YH
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D015854:Up-Regulation / Q000235:genetics
C506897:Spp1 protein, rat; D053495:Osteopontin