The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD.
The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD.
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DOI：
10.1038/s41419-021-03620-z
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发表时间：
2021-03-25
影响因子：
9
通讯作者：
Kim SW
中科院分区：
文献类型：
--
作者：
Kim DH;Park JS;Choi HI;Kim CS;Bae EH;Ma SK;Kim SW
自噬对于细胞分解和回收细胞蛋白质，去除受损的细胞器，特别是对于急性肾损伤（阿基）的恢复非常重要。尽管对自噬在阿基中的作用和细胞机制进行了研究，但自噬在慢性肾脏疾病（CKD）进展中的作用仍然知之甚少。在这里，使用法尼醇X受体（FXR）敲除（KO）小鼠，我们确定FXR是否通过调节肾脏自噬和细胞凋亡来防止肾缺血再灌注（如I/R）损伤后阿基向CKD的进展。FXR调节在进食和禁食条件下参与肾自噬的基因，例如肝自噬，并且通过激动剂例如GW 4064和INT-747激活FXR，减弱缺氧诱导的人肾近端小管上皮（HK 2）细胞的增加的自噬和凋亡。与野生型（WT）小鼠相比，FXR KO小鼠中自噬相关和凋亡相关蛋白的表达水平增加。我们还表明，缺氧处理的HK 2细胞中反应性氧化物质（ROS）的增加通过FXR激动剂处理或FXR过表达而减弱，并且FXR缺陷细胞和小鼠中的ROS水平升高。在I/R损伤后28天，FXR KO小鼠的自噬水平仍然升高，纤维化相关蛋白和ROS沉积的表达水平高于WT小鼠。总之，FXR对肾脏自噬和细胞凋亡的调节可能是早期肾损伤和阿基进展为CKD的治疗靶点。
Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.
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影响因子：
64.8
作者：
Lee, Jae Man;Wagner, Martin;Xiao, Rui;Kim, Kang Ho;Feng, Dan;Lazar, Mitchell A.;Moore, David D.
通讯作者：
Moore, David D.
影响因子：
19.6
作者：
Kaushal GP;Shah SV
通讯作者：
Shah SV
影响因子：
21.3
作者：
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影响因子：
4.6
作者：
Li J;Gao L;Chen S;Tao K;Su Y;Wang T
通讯作者：
Wang T
影响因子：
19.6
作者：
Huls, M.;van den Heuvel, J. J. M. W.;Masereeuw, R.
通讯作者：
Masereeuw, R.