The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.
The molecular phenotype of endocapillary proliferation: novel therapeutic targets for IgA nephropathy.
复制标题
内科毛细血管增殖的分子表型：IgA肾病的新型治疗靶标。
DOI：
10.1371/journal.pone.0103413
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Reich HN
中科院分区：
文献类型：
--
作者：
Hodgin JB;Berthier CC;John R;Grone E;Porubsky S;Gröne HJ;Herzenberg AM;Scholey JW;Hladunewich M;Cattran DC;Kretzler M;Reich HN
IgA 肾病（IgAN）是一种临床和病理上具有异质性的疾病。毛细血管内增殖与进展性疾病的较高风险相关，临床研究表明皮质类固醇可以减轻这种风险。然而，皮质类固醇与多变的细胞效应和显着的毒性有关。此外，它们调节 IgAN 肾损伤的精确机制尚不清楚。为了更好地了解毛细血管内增殖发展所涉及的分子途径并确定新的特异性治疗靶点，我们评估了 22 名 IgAN 患者的显微解剖肾活检的肾小球转录组。毛细血管内增殖由 3 名肾病理学家根据牛津评分系统独立定义。我们使用微阵列分析了 mRNA 表达，并鉴定了与没有毛细血管内病变的 IgAN 患者相比，毛细血管内增殖患者中差异表达的转录本。接下来，我们采用转录因子分析和计算机药物筛选，并证实毛细血管内增殖转录组显着富含可能受皮质类固醇影响的途径。通过这种方法，我们还确定了可考虑用于 IgAN 治疗试验的新治疗靶点和生物活性小分子，包括白藜芦醇和氢奎宁。总之，我们定义了与 IgAN 进行性肾功能不全相关的病理表型的独特分子特征。对毛细血管内增殖相关途径的探索证实了皮质类固醇在 IgAN 亚组中临床有效性的分子基础，并阐明了 IgAN 的新治疗策略。
IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN.
登录
查看更多内容
影响因子：
13.2
作者：
Bartosik, LP;Lajoie, G;Cattran, DC
通讯作者：
Cattran, DC
影响因子：
56.9
作者：
AUPHAN, N;DIDONATO, JA;KARIN, M
通讯作者：
KARIN, M
影响因子：
13.2
作者：
Hotta, O;Furuta, T;Taguma, Y
通讯作者：
Taguma, Y
DOI：
10.3904/kjim.2012.27.3.293
发表时间：
2012-09
期刊：
The Korean journal of internal medicine
影响因子：
--
作者：
Lee H;Yi SH;Seo MS;Hyun JN;Jeon JS;Noh H;Han DC;Hwang SD;Jin SY;Kwon SH
通讯作者：
Kwon SH
影响因子：
39.2
作者：
Levey AS;Stevens LA;Schmid CH;Zhang YL;Castro AF 3rd;Feldman HI;Kusek JW;Eggers P;Van Lente F;Greene T;Coresh J;CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
通讯作者：
CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)