Prevention of C5 activation ameliorates spontaneous and experimental factor H-deficient glomerulonephritis in mice
Prevention of C5 activation ameliorates spontaneous and experimental factor H-deficient glomerulonephritis in mice
复制标题
DOI：
10.1073/pnas.0601094103
复制
发表时间：
2006-06-20
影响因子：
11.1
通讯作者：
Botto, M.
中科院分区：
文献类型：
--
作者：
Pickering, M. C.;Warren, J.;Botto, M.
膜增生性肾小球肾炎（MPGN）II型（致密存款病）是一种以肾小球基底膜上的电子致密沉积物和补体C3为特征的炎性肾病。没有有效的治疗方法。我们研究了C5激活在MPGN模型中的作用，该模型在补体因子H缺陷小鼠（Cfh（-/-））中自发发展。在12个月时，C5缺陷的Cfh（-/-）小鼠的死亡率、肾小球细胞构成、中性粒细胞数量和血清肌酐水平显著降低。在给予抗肾小球基底膜抗体后，在Cfh（-/-）小鼠中也观察到肾小球中性粒细胞数量过多，这在MPGN患者疾病发作期间常见。这种夸大的损伤表型在C5缺陷的Cfh（-/-）小鼠中不存在，但在C6缺陷的Cfh（-/-）小鼠中不存在，表明C5活化在诱导肾损伤中的关键作用。重要的是，肾损伤在用抗鼠C5抗体预处理的Cfh（-/-）小鼠中完全逆转。这些结果表明，C5在自发性MPGN和实验诱导的肾炎因子H缺陷小鼠的重要作用，并提供了初步证据，C5抑制治疗可能是有用的人MPGN II型。
Membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease) is an inflammatory renal disease characterized by electron-dense deposits and complement C3 on the glomerular basement membrane. There is no effective therapy. We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh(-/-)). At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels in Cfh(-/-) mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed in Cfh(-/-) mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent in Cfh(-/-) mice deficient in C5 but not in Cfh(-/-) mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed in Cfh(-/-) mice pretreated with an anti-murine C5 antibody. These results demonstrate an important role for C5 in both spontaneous MPGN and experimentally induced nephritis in factor H-deficient mice and provide preliminary evidence that C5 inhibition therapy might be useful in human MPGN type II.