Aa. Eddy et al., RENAL EXPRESSION OF GENES THAT PROMOTE INTERSTITIAL INFLAMMATION AND FIBROSIS IN RATS WITH PROTEIN-OVERLOAD PROTEINURIA, Kidney international, 47(6), 1995, pp. 1546-1557
Rats with significant proteinuria induced by daily injections of bovin
e serum albumin develop interstitial inflammation and fibrosis. The pr
esent study was designed to investigate the molecular basis of interst
itial monocyte (M0) recruitment and early interstitial fibrosis. Group
s of rats were sacrificed after one, two and three weeks. Despite an i
ncrease in interstitial M0 at week 1, whole kidney mRNA levels were no
t elevated for monocyte chemoattractant protein-1 (MCP-1), osteopontin
or vascular cell adhesion molecule-1 (VCAM-1). Only osteopontin mRNA
levels were significantly elevated in the renal cortex at four days. A
t two and three weeks, MCP-1 and osteopontin mRNA levels were increase
d and the proteins showed distinct tubular patterns of distribution. B
y immunostaining increased expression of VCAM-1 and intercellular adhe
sion molecule-1 (ICAM-1) was restricted to their presence or the surfa
ce of the interstitial inflammatory cells. TGF-beta 1 mRNA levels were
increased at weeks 1, 2 and 3 (2.1, 2.9, 3.6x); interstitial and occa
sional cortical tubular cells expressed TGF-beta 1 mRNA and protein. T
here was a progressive rise in the number of cortical interstitial fie
lds with increased staining for collagen (col) 1 (18, 29, 44%), col II
I (39, 61, 63%), col IV (7, 13, 29%), laminin (4, 10, 30%), fibronecti
n (14, 28, 37%), tenascin (19, 22, 14%) and in total renal col measure
d biochemically (1.1, 1.4, 2.0x) at weeks 1, 2 and 3, respectively. Re
nal matrix protein mRNA levels were variable and not always predictive
of fibrosis. Only col I and tenascin levels were increased at week 1;
all matrix protein mRNA levels except col IV were increased at week 2
; but only tenascin, laminin and col IV mRNA levels remained elevated
at three weeks. Plasminogen activator inhibitor-1 (PAI-1) and tissue i
nhibitor of metalloproteinases (TIMP)-1 mRNA levels were significantly
increased at two weeks. During the three weeks there was no change in
urokinase, stromelysin or TIMP-3 mRNA levels. These results suggest t
hat both increased matrix protein synthesis and altered matrix remodel
ing/degradation contribute to the final interstitial fibrogenic proces
s in rats with protein-overload proteinuria. M0, one of the sources of
TGF-beta 1, infiltrate the interstitium by complex recruitment mechan
isms which may depend in part on osteopontin, ICAM-1 and VCAM-1 expres
sion.