JAK inhibition in the treatment of diabetic kidney disease.
JAK inhibition in the treatment of diabetic kidney disease.
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DOI：
10.1007/s00125-016-4021-5
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发表时间：
2016-08
期刊：
影响因子：
8.2
通讯作者：
Kretzler M
中科院分区：
文献类型：
--
作者：
Brosius FC;Tuttle KR;Kretzler M
糖尿病肾病 (DKD) 是当今许多国家肾衰竭的最常见原因，但过去 20 年来治疗方法并没有改善。最近，系统生物学方法已经能够阐明参与 DKD 进展的信号通路和网络，而这些信号通路和网络以前并未得到充分认识。与 DKD 进展密切相关的一个重要途径是 Janus 激酶信号转导和转录激活剂 (JAK-STAT) 途径。在早期和进行性 DKD 中，肾脏多个细胞（包括肾小球足细胞）中 JAK-STAT 基因的表达增加。随后在小鼠糖尿病模型中进行的实验表明，选择性增强肾小球足细胞中 JAK2 的表达可增加 DKD 的功能和病理特征。最后，一项尚未发表的 2 期多中心、随机、双盲、安慰剂对照研究已在患有 DKD 的 2 型糖尿病参与者中进行，研究选择性 JAK1 和 JAK2 抑制剂的疗效。在这项试验中，与接受安慰剂的参与者相比，接受活性抑制剂的参与者的蛋白尿有所减少。这些结果支持进一步研究 JAK 抑制剂作为 DKD 的新疗法。本综述总结了 2015 年 EASD 年会上“糖尿病的抗炎干预”研讨会上的演讲。会议主席 Hiddo Heerspink (DOI: XXX) 对此进行了概述。
Diabetic kidney disease (DKD) is the most common cause of kidney failure in many countries today, but treatments have not improved in the last 20 years. Recently, systems biology methods have allowed the elucidation of signalling pathways and networks involved in the progression of DKD that were not well appreciated previously. A prominent pathway found to be integrally associated with DKD progression is the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway. Increased expression of JAK–STAT genes was found in multiple cells in the kidney, including glomerular podocytes, in both early and progressive DKD. Subsequent experiments in a mouse diabetic model showed that enhanced expression of JAK2 selectively in glomerular podocytes increased functional and pathological features of DKD. Finally, a yet unpublished Phase 2 multicentre, randomised, double-blind, placebo-controlled study of the efficacy of a selective JAK1 and JAK2 inhibitor has been conducted in type 2 diabetic participants with DKD. In this trial there was a reduction of albuminuria in participants who received the active inhibitor compared with those who received a placebo These results support the further study of JAK inhibitors as a new therapy for DKD. This review summarises a presentation given at the ‘Anti-inflammatory interventions in diabetes’ symposium at the 2015 annual meeting of the EASD. It is accompanied by an overview by the Session Chair, Hiddo Heerspink (DOI: XXX).