阻断CD40-CD40配体可预防慢性蛋白尿性肾病中的肾损伤。

Blockade of CD40-CD40 ligand protects against renal injury in chronic proteinuric renal disease.

作者信息

Kairaitis Lukas, Wang Yiping, Zheng Ling, Tay Yuet-Ching, Wang Yang, Harris David C H

机构信息

Department of Renal Medicine, The University of Sydney at Westmead Hospital, Westmead, Sydney, Australia.

出版信息

Kidney Int. 2003 Oct;64(4):1265-72. doi: 10.1046/j.1523-1755.2003.00223.x.

DOI:10.1046/j.1523-1755.2003.00223.x

PMID:12969144

Abstract

BACKGROUND

Interaction between CD40 and CD40 ligand (CD40L) is involved in both cognate and innate immune responses. Blockade of CD40-CD40L interactions reduces severity of renal injury in murine lupus nephritis and membranous nephropathy. We hypothesized that CD40-CD40L could contribute to renal injury in models that are not antibody-dependent, and that anti-CD40L could diminish inflammation and fibrosis in murine adriamycin nephropathy.

METHODS

Male BALB/c mice were divided into three groups (N = 6 per group): (1). saline-treated, age-matched control; (2). adriamycin only; and (3). MR1 + adriamycin. In group 3, mice were treated with intraperitoneal injections of anti-CD40L antibody (clone MR1, 0.4 mg per mouse) after the onset of proteinuria at days 5, 7, 9, and 11 after adriamycin treatment. Animal subgroups were compared at 14 and 42 days after induction of adriamycin nephropathy. Functional and pathologic markers of disease severity, cellular components of interstitial inflammation, and the degree of CD40 expression were assessed. Relative cortical RNA expression of the chemokine monocyte-chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) was also compared between animal groups.

RESULTS

CD40 was weakly expressed in tubules of normal mice but was expressed in tubules, interstitium, and glomeruli of mice with adriamycin nephropathy in a time-dependent manner. MR1 treatment resulted in a significant attenuation of the severity of adriamycin nephropathy at day 42 [e.g., glomerular sclerosis (%), group 3, 20.1 +/- 4.7 vs. group 2, 30.2 +/- 7.2, P < 0.001]. CD40L blockade significantly reduced tubulointerstitial injury as well [tubular diameter microm), group 3, 42.5 +/- 6.9 vs. group 2, 66.3 +/- 13.7, P < 0.001; and group 1, 37.3 +/- 5.7, P < 0.01; tubular cell height microm), group 3, 16.3 +/- 1.7 vs. group 2, 11 +/- 1.8, P < 0.01; and group 1, 18.2 +/- 1.9, P < 0.01; interstitial volume (%), group 3, 13.9 +/- 5.1 vs. group 2, 26.2 +/- 4.9, P < 0.001; and group 1, 1.3 +/- 0.7, P < 0.001; proteinuria (mg/24 hours), group 3, 1.8 +/- 0.6 vs. group 2, 4.3 +/- 0.8, P < 0.001; and group 1, 0.7 +/- 0.2, P < 0.05; and creatinine clearance microL/min), group 3, 75 +/- 4 vs. group 2, 35 +/- 2, P < 0.001; and group 1, 82 +/- 4, P < 0.01] were also improved by MR1. MR1 treatment also resulted in a significant reduction in the number of cortical macrophages at both 14 and 42 days after adriamycin (P < 0.01). Cortical expression of MCP-1 and RANTES was significantly reduced by MR1 treatment at 42 days after adriamycin (P < 0.01 and P < 0.05, respectively).

CONCLUSION

Blockade of CD40-CD40L interaction protects against renal structural and functional injury in this murine model of chronic proteinuric renal disease.

摘要

背景

CD40与CD40配体（CD40L）之间的相互作用参与了同源免疫反应和固有免疫反应。阻断CD40 - CD40L相互作用可降低小鼠狼疮性肾炎和膜性肾病的肾损伤严重程度。我们推测，在非抗体依赖性模型中，CD40 - CD40L可能导致肾损伤，并且抗CD40L可以减轻小鼠阿霉素肾病中的炎症和纤维化。

方法

将雄性BALB/c小鼠分为三组（每组N = 6）：（1）生理盐水处理的年龄匹配对照组；（2）仅阿霉素组；（3）MR1 + 阿霉素组。在第3组中，阿霉素治疗后第5、7、9和11天出现蛋白尿时，小鼠腹腔注射抗CD40L抗体（克隆MR1，每只小鼠0.4 mg）。在阿霉素肾病诱导后14天和42天对动物亚组进行比较。评估疾病严重程度的功能和病理标志物、间质炎症的细胞成分以及CD40表达程度。还比较了动物组之间趋化因子单核细胞趋化蛋白-1（MCP-1）和活化正常T细胞表达和分泌调节因子（RANTES）的相对皮质RNA表达。

结果

CD40在正常小鼠肾小管中弱表达，但在阿霉素肾病小鼠的肾小管、间质和肾小球中呈时间依赖性表达。MR1治疗在第42天导致阿霉素肾病严重程度显著减轻[例如，肾小球硬化（%），第3组，20.1±4.7 vs.第2组，30.2±7.2，P < 0.001]。CD40L阻断也显著减轻了肾小管间质损伤[肾小管直径（微米），第3组，42.5±6.9 vs.第2组，66.3±13.7，P < 0.001；第1组，37.3±5.7，P < 0.01；肾小管细胞高度（微米），第3组，16.3±1.7 vs.第2组，11±1.8，P < 0.01；第1组，18.2±1.9，P < 0.01；间质体积（%），第3组，13.9±5.1 vs.第2组，26.2±4.9，P < 0.001；第1组，1.3±0.7，P < 0.001；蛋白尿（mg/24小时），第3组，1.8±0.6 vs.第2组，4.3±0.8，P < 0.001；第1组，0.7±0.2，P < 0.05；肌酐清除率（微升/分钟），第3组，75±4 vs.第2组，35±2，P < 0.001；第1组，82±4，P < 0.01]。MR1治疗还导致阿霉素后14天和42天皮质巨噬细胞数量显著减少（P < 0.01）。阿霉素后42天，MR1治疗使皮质MCP-1和RANTES表达显著降低（分别为P < 0.01和P < 0.05）。