研究与评论:医学与健康雷竞技苹果下载科学杂志
菜单ISSN: 2319 - 9865
ISSN: 2319 - 9865
约亨·W·U·弗里斯
德国科隆大学医院
ScientificTracks抽象:RRJMHS
本报告重点介绍了作者实验室在蛋白尿肾病、肾癌和小管毒性中内皮素-1 (ET-1)信号在肾近端小管损伤中的作用，包括miRNAs。MicroRNAs (miRNAs)是一种短的非编码rna，通过靶向蛋白质编码转录物的mRNA序列，在细胞功能和发育中发挥重要作用，导致mRNA的切割或有效翻译的抑制。炎症/肿瘤:作者的研究小组已经证明，ET-1在原发性肾近端小管细胞中作为细胞信号传导的媒介起着重要作用，表达其受体亚型(a, B)。在导致炎症和随后纤维化的膜性肾病或局灶性节段性硬化等蛋白尿疾病以及小管癌细胞(CAKI-1)中，ET-1能够激活由NF-κB p65、MAPK p38α和PKCα组成的细胞质转录复合体。因此，PKCα不再能够在细胞核内转运，这导致primiRNA15a的抑制丧失，该miRNA在细胞质中的成熟，其小管分泌和在尿液中的可检测性丧失。这种机制似乎存在于微小病变、膜性肾病和局灶性节段性硬化中。在体外和阿霉素蛋白尿模型中上调PKCα水平可导致尿中检测不到miRNA15a水平。这可以作为控制治疗效果和依从性的标志。在肾肿瘤中，高miRNA15a水平(以及相应的低PKCα水平)是恶性透明细胞癌的特征，在良性肿瘤细胞瘤中呈负相关。肿瘤切除可改变尿中miRNa15a水平。 Meanwhile, the NF-κB p65 has unrestricted nuclear access, transcribing NF-κB responsive genes. Proliferation/Tumor suppression: miRNa15a induces a splice-form of MAPK p38α, called Mxi-2. We showed that Mxi-2 is a transcription factor in proximal tumor cells. Building a complex with ETS-1 and ERK, it activates p16/p21. Furthermore, in a RISC (RNA-induced silencing complex) in the cytoplasm together with Ago2 and miRNA1285 it blocks nuclear transmigration of p53, indicating a potential block of tumor suppression. Tubulotoxicity: Through evolution, the regulatory induction of the multiple drug resistant protein 2 (MRP2) via ET-1 receptor B (ETBR) is known. We showed that in an Adriamycin model as well as in human biopsies of proteinuric disease, MRP2 is downregulated. This regulation occurs via ET-1 stimulation of ETBR and activation of miRNA133a, interacting with the 3’UTR region of the MRP2 gene. The excretion of this miRNA could be used as surrogate marker for MRP2 downregulation. This mechanism is also explains tubulotoxicity in renal transplant patients treated with cyclosporine A (CyA): MRP2 responsible for tubular excretion is downregulated in CyA tubulotoxic damage as shown by quantitative immune histology of MRP2 vs. controls (CyAarteriolopathy, CyA non-affected transplants, and normal kidneys). miRNAs could be useful as (i) biomarkers in the urine for renal carcinoma; (ii) indicators of activated signaling pathways in proteinuric disease; (iii) as surrogate marker for potential tubulotoxicity, particularly when tubulotoxic drugs like CyA are considered as treatment in proteinuric diseases such as pediatric FSGS.
Jochen Fries教授是德国科隆大学医院转化病理学实验室的负责人，专注于内皮素- 1的作用，其信号转导及其新定义的靶基因在肾脏和泌尿生殖病理中的功能。在慢性肾脏疾病、心脏病/血管疾病、分子治疗/移植技术、干细胞技术等领域发表研究论文60余篇。他曾在Brigham and Women 's Hospital接受外科病理学培训，并在Brigham and Women 's Hospital、Children 's Hospital和Harvard School of Public Health获得博士后培训。
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