JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes
JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes
复制标题
JAK/STAT通路通过足细胞自噬促进糖尿病肾病进展
DOI：
10.1016/j.ejphar.2021.174121
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发表时间：
2021-04-30
影响因子：
5
通讯作者：
Wu, Junbiao
中科院分区：
文献类型：
--
作者：
Chen, Dandan;Liu, Yaoyu;Wu, Junbiao
糖尿病肾病（DKD）是糖尿病的主要微血管并发症之一，也是终末期肾病的重要原因。已有研究表明足细胞自噬损伤与DKD的发病机制有关，这种损伤由Janus激酶（JAK）/信号转导子和转录（STAT）信号通路密切介导。在这里，JAK/STAT信号通路调节足细胞自噬的潜在分子机制进行了研究。在本研究中，与对照组相比，DKD小鼠表现出肾小球肥大、肾脏重量/重量比增加、尿蛋白水平增加以及结蛋白和突触蛋白表达减少。同时，DKD小鼠血清中甘油三酯、总胆固醇、还原型谷胱甘肽和丙二醛水平也升高。此外，在DKD小鼠中观察到较低数量的自噬体，肾小球中MAP 1 LC 3（LC 3）的表达减少，以及JAK/STAT通路相关蛋白，即JAK 1、JAK 2、STAT 1、STAT 3、STAT 5和STAT 6的表达增加。在体外实验中，我们观察到在高糖条件下足细胞自噬受损，凋亡增强，JAK/STAT通路激活。使用ruxolitinib抑制剂的研究表明，在高葡萄糖条件下抑制足细胞中的JAK/STAT通路可以增加自噬通量和自噬相关蛋白的表达。综上所述，本研究表明，高葡萄糖通过激活小鼠和足细胞中的JAK/STAT通路来抑制自噬，从而阻止从体内有效清除受损蛋白质和细胞器以防止细胞凋亡，并最终加重足细胞损伤和DKD的进展。
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes and an important cause of end-stage renal disease. Previous studies have shown that the damage to podocyte autophagy is related to the pathogenesis of DKD, and this damage is closely mediated by the Janus kinase (JAK)/signal transductors and the transcription (STAT) signaling pathway. Here, the underlying molecular mechanism of the JAK/STAT signaling pathway regulating podocyte autophagy was investigated. In the present study, compared to controls, DKD mice showed glomerular hypertrophy, increased kidney weight/weight ratio, and increased urinary protein levels, as well as decreased desmin and synaptopodin expression. Meanwhile, levels of triglyceride, total cholesterol, reduced glutathione, and malondialdehyde were also increased in the serum of DKD mice. Further, a lower number of autophagosomes, reduced expression of MAP1LC3 (LC3) in glomeruli, and increased expression of JAK/STAT pathway-related proteins, namely JAK1, JAK2, STAT1, STAT3, STAT5, and STAT6, were observed in DKD mice. In the in vitro experiments, we observed impaired autophagy, enhanced apoptosis, and activated JAK/STAT pathway in podocytes under high glucose conditions. Studies using ruxolitinib inhibitors have showed that suppression of the JAK/STAT pathway in podocytes subjected to high glucose could increase autophagic flux and autophagy-related protein expression. Taken together, the present study demonstrates that high glucose inhibits autophagy by activating the JAK/STAT pathway in mice and podocytes, thereby preventing the efficient removal of damaged proteins and organelles from the body to prevent apoptosis, and ultimately aggravating the progression of podocyte injury and DKD.