Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice.
Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice.
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DOI：
10.1371/journal.pone.0008474
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发表时间：
2009-12-29
期刊：
影响因子：
3.7
通讯作者：
Rekvig OP
中科院分区：
文献类型：
--
作者：
Fenton K;Fismen S;Hedberg A;Seredkina N;Fenton C;Mortensen ES;Rekvig OP
狼疮性肾炎的特征是染色质片段-IgG复合物在系膜基质和肾小球基底膜（GBM）中的沉积。后者定义为终末期疾病。在本研究中，我们确定的影响抗体双链DNA，肾DNase 1和基质金属蛋白酶（MMP）的mRNA水平和酶活性的早期和晚期事件在小鼠狼疮肾炎。主要的重点是分析这些因素是否相互关联，以及它们的表达变化是否解释了狼疮肾炎的基本过程。肾炎的早期阶段与系膜基质中的染色质-IgG复合物沉积有关。一个引人注目的观察结果是，该事件与抗dsDNA抗体的出现和轻度或临床无症状肾炎相关。这些事件发生在肾Dnase 1下调之前。随后，肾脏Dnase 1 mRNA水平和酶活性降低，而MMP 2 mRNA水平和酶活性升高。肾Dnase 1水平的降低与死亡细胞染色质碎片的缺乏有关。大片段被保留并积累在GBM中。此外，由于染色质片段倾向于刺激例如树突细胞中的Toll样受体，这实际上可以解释MMP的表达增加。这些情况可以解释的基础上沉积的染色质-IgG复合物在肾小球的早期和晚期阶段的肾炎，肾小球的完整性损失，最后肾功能衰竭。
Lupus nephritis is characterized by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes (GBM). The latter defines end-stage disease. In the present study we determined the impact of antibodies to dsDNA, renal Dnase1 and matrix metalloprotease (MMP) mRNA levels and enzyme activities on early and late events in murine lupus nephritis. The major focus was to analyse if these factors were interrelated, and if changes in their expression explain basic processes accounting for lupus nephritis. Early phases of nephritis were associated with chromatin-IgG complex deposition in the mesangial matrix. A striking observation was that this event correlated with appearance of anti-dsDNA antibodies and mild or clinically silent nephritis. These events preceded down-regulation of renal Dnase1. Later, renal Dnase1 mRNA level and enzyme activity were reduced, while MMP2 mRNA level and enzyme activity increased. Reduced levels of renal Dnase1 were associated in time with deficient fragmentation of chromatin from dead cells. Large fragments were retained and accumulated in GBM. Also, since chromatin fragments are prone to stimulate Toll-like receptors in e.g. dendritic cells, this may in fact explain increased expression of MMPs. These scenarios may explain the basis for deposition of chromatin-IgG complexes in glomeruli in early and late stages of nephritis, loss of glomerular integrity and finally renal failure.
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影响因子：
4.4
作者：
Deocharan, B;Qing, XP;Putterman, C
通讯作者：
Putterman, C
DOI：
10.1080/10253890701314863
发表时间：
2007-11-01
影响因子：
2.3
作者：
Gesualdi, N. Montesano;Chirico, G.;Esposito, F.
通讯作者：
Esposito, F.
影响因子：
12.8
作者：
Lim, Eun-Jung;Lee, Sun-Hye;Lee, ChuHee
通讯作者：
Lee, ChuHee
影响因子：
4
作者：
Dai, Yong;Sui, Weiguo;Huang, YuanShuai
通讯作者：
Huang, YuanShuai
影响因子：
32.4
作者：
Christensen, Sean R.;Shupe, Jonathan;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.