Estrogen Receptor α Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity.
Estrogen Receptor α Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity.
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DOI：
10.4049/jimmunol.1700770
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发表时间：
2018-01-15
期刊：
影响因子：
--
通讯作者：
Caricchio R
中科院分区：
文献类型：
--
作者：
Corradetti C;Jog NR;Cesaroni M;Madaio M;Caricchio R
肾小球肾炎（GN）是系统性红斑狼疮（SLE）最严重的表现之一。由于SLE在女性中的发病率至少高出10倍，因此长期以来人们一直怀疑雌激素在疾病发病机制中的作用。雌激素受体α (ERα)在肾组织中高表达。我们询问ERα表达是否有助于狼疮肾炎等免疫介导肾病的发展。我们通过卵清蛋白免疫和诱导雌性er α - ko小鼠慢性移植物抗宿主病，测试了雌激素受体对免疫反应的总体影响。我们使用肾毒性血清肾炎（NTN）作为免疫介导肾病的模型。我们通过对肾小球提取物基因表达的微阵列分析来研究ERα对肾炎过程中分子通路的影响。我们对狼疮患者全血进行了RNA测序，以确定小鼠和人类肾炎的共同途径。尽管肾脏中存在免疫复合物和促炎细胞因子的产生，以及对免疫的正常体液反应，但缺乏雌激素受体α可保护雌性小鼠免于发生肾炎。NTN期间肾小球的时间过程微阵列分析显示，与er α - ko女性相比，WT女性中ppar介导的脂质代谢相关基因显著上调，视黄醇代谢相关基因显著下调。同样，狼疮患者血液的RNA测序也揭示了这些相同途径的相似表达模式。在肾炎期间，代谢途径活性的改变，如视黄醇代谢，发生在ERα激活的下游，是进展到终末期肾衰竭的必要条件。
Glomerulonephritis (GN) is one of the most serious manifestations of systemic lupus erythematous (SLE). Because SLE is at least ten times more common in women, a role for estrogens in disease pathogenesis has long been suspected. Estrogen receptor alpha (ERα) is highly expressed in renal tissue. We asked whether ERα expression contributes to the development of immune-mediated nephropathies like in lupus nephritis. We tested the overall effects of estrogen receptors on the immune response by immunization with ovalbumin and induction of chronic graft versus host disease in female ERαKO mice. We used Nephrotoxic serum nephritis (NTN) as a model of immune mediated nephropathy. We investigated the influence of ERα on molecular pathways during nephritis by microarray analysis of glomerular extract gene expression. We performed RNA sequencing of lupus patient whole blood to determine common pathways in murine and human nephritis. Absence of estrogen receptor alpha protects female mice from developing nephritis, despite the presence of immune complexes and production of pro-inflammatory cytokines in the kidneys, and normal humoral responses to immunization. Time-course microarray analysis of glomeruli during NTN revealed significant up-regulation of genes related to PPAR-mediated lipid metabolism and downregulation of genes in the retinol metabolism in WT females compared to ERαKO females. Similarly, RNA sequencing of lupus patients blood revealed similar expression patterns of these same pathways. During nephritis, the altered activity of metabolic pathways, such as retinol metabolism, occurs downstream of ERα activation and is essential for the progression to end-stage renal failure.
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DOI：
10.1093/bioinformatics/btr490
发表时间：
2011-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Howe EA;Sinha R;Schlauch D;Quackenbush J
通讯作者：
Quackenbush J
影响因子：
19.6
作者：
Doublier S;Lupia E;Catanuto P;Periera-Simon S;Xia X;Korach K;Berho M;Elliot SJ;Karl M
通讯作者：
Karl M
影响因子：
5
作者：
Bynote, K. K.;Hackenberg, J. M.;Gould, K. A.
通讯作者：
Gould, K. A.
DOI：
10.1111/j.1749-6632.1997.tb52046.x
发表时间：
1997-01-01
期刊：
B LYMPHOCYTES AND AUTOIMMUNITY
影响因子：
--
作者：
Chan, O;Madaio, MP;Shlomchik, MJ
通讯作者：
Shlomchik, MJ
影响因子：
0.7
作者：
Dushkin, M. I.;Khoshchenko, O. M.;Schvarts, Y. Sh.
通讯作者：
Schvarts, Y. Sh.