Effects of complement factor D deficiency on the renal disease of MRL/lpr mice
Effects of complement factor D deficiency on the renal disease of MRL/lpr mice
复制标题
DOI：
10.1111/j.1523-1755.2004.00371.x
复制
发表时间：
2004-01-01
影响因子：
19.6
通讯作者：
Gilkeson, GS
中科院分区：
文献类型：
--
作者：
Elliott, MK;Jarmi, T;Gilkeson, GS
背景补体旁路途径（AP）在狼疮性肾炎个体和系统性红斑狼疮鼠模型（包括MRL/lpr小鼠）中被激活。我们实验室先前的一项研究评价了B因子（Bf-/-）遗传缺陷的MRL/lpr小鼠（AP活化所必需的蛋白质）的肾脏疾病发展。MRL/lpr Bf-/-小鼠发生的肾脏疾病较少，存活率提高;然而，由于Bf基因位于MHC基因复合体中，这些小鼠的主要组织相容性复合体（MHC）单倍型（H-2（B））也不同于其野生型同窝小鼠（H-2（k））。我们进行了目前的研究，以确定是否减少肾脏疾病的MRL/lpr Bf-/-小鼠是由于缺乏AP激活或H-2（B）单倍型通过研究D因子（Df）缺乏的影响，AP激活的关键蛋白，疾病的发展在MRL/lpr小鼠。将Df缺陷小鼠与MRL/lpr小鼠回交4至9代。评价MRL/lpr H-2（k）Df-/-、Df+/-和Df +/+同窝仔的疾病发展。通过酵母聚糖测定确定MRL/lpr Df-/-小鼠中AP活化的缺乏。使用肌酸酐试剂盒测量血清肌酸酐水平。蛋白尿和自身抗体水平测定酶联免疫吸附试验（ELISA）。用异硫氰酸荧光素（FITC）α-鼠C3或α-鼠IgG对一个肾脏的切片进行染色，以检测C3和IgG沉积。将剩余的肾脏切成两半，一半固定，切片，用苏木精和伊红和高碘酸-希夫（PAS）染色以评估病理学，另一半固定在戊二醛中并通过电子显微镜检查。MRL/lpr Df-/-小鼠的肾小球IgG沉积、蛋白尿和自身抗体水平与Df+/+和Df+/-同窝小鼠相似。然而，Df-/-小鼠的肾小球C3沉积、血清肌酐水平和病理性肾脏疾病显著减少。尽管Df-/-小鼠没有肾脏疾病，但寿命不受D因子缺乏的影响。Df和AP活化的缺乏对MRL/lpr小鼠中增殖性肾病的发展具有保护作用，表明MRL/lpr小鼠中Bf缺乏的类似作用也是由于缺乏AP活化。
Background. The alternative complement pathway (AP) is activated in individuals with lupus nephritis and in murine models of systemic lupus erythematosus, including MRL/lpr mice. A previous study from our laboratory evaluated the development of renal disease in MRL/lpr mice genetically deficient in factor B (Bf-/-), a protein necessary for AP activation. MRL/lpr Bf-/- mice developed less renal disease and had improved survival; however, these mice were also a different major histocompatibility complex (MHC) haplotype (H-2(b)) than their wild-type littermates (H-2(k)) due to the gene for Bf being located in the MHC gene complex. We undertook the current study to determine if the decreased renal disease in MRL/lpr Bf-/- mice was due to the lack of AP activation or the H-2(b) haplotype by studying the effects of factor D(Df) deficiency, a critical protein for AP activation, on disease development in MRL/lpr mice.Methods. Df-deficient mice were backcrossed with MRL/lpr mice for four to nine generations. MRL/lpr H-2(k) Df-/-,Df+/-, and Df +/+ littermates were evaluated for disease development. Lack of AP activation in MRL/lpr Df-/- mice was determined by the zymosan assay. Serum creatinine levels were measured using a creatinine kit. Proteinuria and autoantibody levels were determined by enzyme-linked immunosorbent assay (ELISA). Sections from one kidney were stained with fluorescein isothiocyanate (FITC) alpha-murine C3 or alpha-murine IgG to detect C3 and IgG deposition. The remaining kidney was cut in half with one half fixed, sectioned, and stained with hematoxylin and eosin and periodic acid-Schiff (PAS) to evaluate pathology and another half fixed in glutaraldehyde and examined via electron microscopy.Results. MRL/lpr Df-/- mice had similar glomerular IgG deposition, proteinuria and autoantibody levels, as Df+/+ and Df+/- littermates. However, glomerular C3 deposition, serum creatinine levels, and pathologic renal disease were significantly reduced in Df-/- mice. Despite the lack of renal disease in Df-/- mice, life span was not impacted by factor D deficiency.Conclusion. The absence of Df and AP activation is protective against the development of proliferative renal disease in MRL/lpr mice suggesting the similar effect of Bf deficiency in MRL/lpr mice was also due to the lack of AP activation.