Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice
Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice
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DOI：
10.1097/01.asn.0000130082.67775.60
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发表时间：
2004-06-01
影响因子：
13.6
通讯作者：
Schlöndorff, D
中科院分区：
文献类型：
--
作者：
Anders, HJ;Belemezova, E;Schlöndorff, D
慢性进行性肾损害是终末期肾病的主要原因。采用自身免疫性肾小球肾炎MRL1PR/1PR小鼠进行性免疫复合体肾炎模型，探讨趋化因子受体CCR1在病程晚期阻断是否会影响肾功能衰竭的进展。从20到24周龄的小鼠，每周三次皮下注射赋形剂或非肽CCR1拮抗剂BX471。BX471可提高血尿素氮水平(BX471，35.1+/-5.3；Vehicle；73.1+/-39.6 mg/dl；P<；0.05)，减少肾间质中ERHR-3巨噬细胞、CD3淋巴细胞、Ki-67阳性增殖细胞和单链DNA阳性凋亡细胞的数量。用赋形剂或BX471处理的荧光标记T细胞的细胞转移研究表明，BX471阻止巨噬细胞和T细胞募集到MRL1pr/1PR小鼠的肾间质。这与CC趋化因子CCL2、CCL3、CCL4和CCL5以及趋化因子受体CCR1、CCR2和CCR5的表达减少有关。此外，BX471还减轻了间质纤维化的程度，通过间质平滑肌肌动蛋白表达和I型胶原沉积以及I型胶原和转化生长因子-β的mRNA表达来评估。BX471不影响MRL1pr/1PR小鼠的血清DNA自身抗体、蛋白尿或肾小球损伤标志物。这是第一个证据表明，在晚期慢性肾损伤中，阻断CCR1可以通过选择性地抑制间质白细胞募集和纤维化来阻止疾病进展和改善肾功能。
Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL1pr/1pr mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a week from week 20 to 24 of age. BX471 improved blood urea nitrogen levels (BX471, 35.1 +/- 5.3; vehicle; 73.1 +/- 39.6 mg/dl; P < 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL1pr/1pr mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-beta. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL1pr/1pr mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.