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From the Departments of Nephrology and Medicine,*
Monash
Medical Centre, Monash University, Clayton, Australia; the Department
of Nephrology,
The First Hospital, Sun Yat-Sen
University of Medical Sciences, Guangzhou, China; and the Division of
Nephrology,
University of Washington Medical
School, Seattle, Washington
Osteopontin (OPN) is a macrophage chemotactic and adhesion molecule
that acts to promote macrophage infiltration in rat anti-glomerular
basement membrane (GBM) glomerulonephritis. The present study
investigated the role of interleukin-1 (IL-1) in the up-regulation of
renal OPN expression in this disease model. Accelerated anti-GBM
glomerulonephritis was induced in groups of six rats. Animals were
treated by a constant infusion of the IL-1 receptor antagonist or
saline (control) over days -1 to 14 (induction phase) or days 7 to 21
(established disease). In normal rat kidney, OPN was expressed
in a few tubules (<5%) and absent from glomeruli. During the
development of rat anti-GBM disease (days 7 to 21), there was
substantial up-regulation of OPN mRNA and protein expression in
glomeruli (>5 cells per glomerular cross-section) and tubular
epithelial cells (50–75% OPN-positive). Up-regulation of OPN
expression was associated with macrophage accumulation within the
kidney, severe proteinuria, loss of renal
function, and severe histological damage including glomerular
crescentic formation and tubulointerstitial fibrosis. In
contrast, IL-1 receptor antagonist treatment of either the
induction phase of disease or established disease significantly reduced
OPN mRNA and protein expression in glomeruli (
75–85%,
P < 0.001) and tubules (45–60%,
P < 0.001). The reduction in OPN expression was
associated with significant inhibition of macrophage accumulation and
progressive renal injury. In vitro, the addition
of IL-1 to the normal rat tubular epithelial cell line NRK52E
up-regulated OPN mRNA and protein levels, an effect that was
dose-dependent and inhibited by the addition of IL-1 receptor
antagonist, thus demonstrating that IL-1 can act directly to
up-regulate renal OPN expression. In conclusion, this study
provides in vivo and in vitro evidence
that IL-1 up-regulates OPN expression in experimental kidney disease
and support for the argument that inhibition of OPN expression is one
mechanism by which IL-1 receptor antagonist treatment suppresses
macrophage-mediated renal injury.
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