Rats with significant
proteinuria induced by daily
injections of
bovine serum albumin develop interstitial
inflammation and
fibrosis. The present study was designed to investigate the molecular basis of interstitial monocyte (Mø) recruitment and early interstitial
fibrosis. Groups of rats were sacrificed after one, two and three weeks. Despite an increase in interstitial Mø at week 1, whole kidney
mRNA levels were not 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. At two and three weeks, MCP-1 and
osteopontin mRNA levels were increased and the
proteins showed distinct tubular patterns of distribution. By immunostaining increased expression of
VCAM-1 and
intercellular adhesion molecule-1 (ICAM-1) was restricted to their presence or the surface 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 occasional cortical tubular cells expressed
TGF-beta 1 mRNA and
protein. There was a progressive rise in the number of cortical interstitial fields with increased staining for
collagen (col) 1 (18, 29, 44%), col III (39, 61, 63%), col IV (7, 13, 29%),
laminin (4, 10, 30%),
fibronectin (14, 28, 37%),
tenascin (19, 22, 14%) and in total renal col measured biochemically (1.1, 1.4, 2.0x) at weeks 1, 2 and 3, respectively. Renal 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 inhibitor of metallo-
proteinases (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 that both increased matrix
protein synthesis and altered matrix remodeling/degradation contribute to the final interstitial fibrogenic process in rats with
protein-overload
proteinuria. Mø, one of the sources of
TGF-beta 1, infiltrate the interstitium by complex recruitment mechanisms which may depend in part on
osteopontin,
ICAM-1 and
VCAM-1 expression.