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

Abstract

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.

• Item Type: Thesis (Dissertation, LMU Munich)
• Keywords: Chemokines, Glomerulosklerosis, CCR1, BX471, Fibrosis
• Dewey Decimal Classification: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: German
• Date Accepted: 09. March 2006
• 1. Referee: Schlöndorff, Detlef
• Persistent Identifier (URN): urn:nbn:de:bvb:19-52189
• Signature of the printed copy: 0700/UMD 11559