Die Blockade des Chemokinrezeptors CCR1 reduziert bei Mäusen mit Adriamycin-induzierter Glomerulosklerose die interstitielle Entzündung und Fibrose

Background. Immigration of leukocytes into inflamed tissue is
mediated by CC chemokines. Blockade of the CC chemokine receptor
CCR1 was shown to reduce interstitial inflammation and fibrosis in
murine obstructive nephropathy. However, it is not known whether
CCR1 blockade is protective in progressive renal injury associated
with severe proteinuria. This study therefore examines the effect
of the small-molecule CCR1 antagonist BX471 in a mur-ine model of
adriamycin-induced focal segmental glomerulosclerosis (FSGS) with
nephrotic syndrome and progressive interstitial inflammation and
fibrosis. Methods. Adriamycin (ADR) nephropathy with persistent
proteinuria was induced in male BALB/c mice by two intravenous
injections of ADR (13 mg/kg) at day 0 and 14. BX471 treatment was
started at day 14 when proteinuria had developed. At 6 weeks, renal
histology was studied by morphometry and immunohistochemistry. The
expression of chemokines was localised by immunohistochemistry and
quantified by RNAse protection assays. The expres-sion of CCR1 in
different leukocyte subsets was quantified by PCR. Results. At week
6, ADR-treated mice showed focal segmental glomerular sclerosis,
associ-ated with tubulointerstitial injury consisting of tubular
dilation and atrophy, interstitial leuko-cyte infiltration and
fibrosis. The mRNA expression of CCR1 and CC chemokines, including
the CCR1 ligands CCL3/MIP-1 and CCL5/RANTES, was upregulated in
diseased kidneys, with a prominent intersitial expression of
CCL5/RANTES. The mayor CCR1-expressing cell subset were
F4/80-positive macrophages. Compared to vehicle-treated controls
BX471 sig-nificantly reduced the amount of macrophages and T
lymphocytes in interstitial lesions by 51 % and 22 %, respectively.
Markers of renal fibrosis such as interstitial fibroblasts (48 %)
and interstitial volume (23 %) were significantly reduced by BX471
treatment. In contrast, the extent of proteinuria and glomerular
sclerosis was not affected by BX471 treatment. Conclusion. Blockade
of CCR1 substantially reduced interstitial leukocyte accumulation
and the subsequent renal fibrosis in a murine model of nephrotic
syndrome and FSGS. These find-ings support a role for CCR1 in
interstitial leukocyte recruitment and suggest that CCR1 blockade
might be a new therapeutic strategy in progressive nephropathies
such as FSGS.