GSK-3β inhibitor TDZD-8 prevents reduction of aquaporin-1 expression via activating autophagy under renal ischemia reperfusion injury
GSK-3β inhibitor TDZD-8 prevents reduction of aquaporin-1 expression via activating autophagy under renal ischemia reperfusion injury
复制标题
GSK-3β抑制剂TDZD-8通过激活肾缺血再灌注损伤下的自噬来防止水通道蛋白-1表达的减少
DOI：
10.1096/fj.202100549r
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发表时间：
2021-08-01
期刊：
影响因子：
4.8
通讯作者：
Li, Chunling
中科院分区：
文献类型：
--
作者：
Liu, Qiaojuan;Kong, Yonglun;Li, Chunling
肾缺血再灌注(I/R)损伤是急性肾损伤(AKI)的主要原因之一。水通道蛋白(AQP)-1在肾脏的水通道对维持水的动态平衡和尿液浓缩能力是至关重要的。越来越多的证据支持自噬在肾I/R所致AKI发病机制中的重要作用。本研究的目的是探讨自噬的激活是否能阻止肾I/R所致AQP1蛋白的下调及其可能的分子机制。大鼠肾脏I/R后，AQP1、2、3以及钠转运体Na+-K+-2Cl(-)共转运体和α-Na，K-ATPase蛋白表达持续下降，这与尿量增加和内生肌酐清除量下降有关。肾脏I/R还抑制了自噬，增加了肾脏的炎症反应。糖原合成酶-3β抑制剂4-Benzyl-2-methyl-1，2，4-thiadiazolidine-3，5-di-8可减轻大鼠肾脏I/R损伤，激活自噬，显著增加肾脏水通道蛋白和钠转运体的表达，从而改善大鼠的尿量和内生肌酐清除量。低氧/复氧(H/R)可抑制小鼠内髓质集合管3(IMCD3)细胞的自噬和下调AQP1的表达，TDZD-8可完全阻止这一作用。3-甲基腺嘌呤或ATG5基因敲除抑制自噬可减弱TDZD-8诱导的H/R IMCD3细胞AQP1蛋白表达的恢复。白介素1β(IL-1β)降低IMCD3细胞AQP1蛋白的丰度。缺氧再灌注可诱导NOD样受体PYR3和IL-1β蛋白表达增加，TDZD-8可逆转这一作用。总之，TDZD-8治疗可通过激活自噬和减少IL-1β的产生来阻止肾I/R损伤时AQP1表达的下调。
Renal ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI). Aquaporin (AQP)-1 water channel in the kidney is critical for the maintenance of water homeostasis and the urinary concentrating ability. Increasing evidence supports an important role of autophagy in the pathogenesis of AKI induced by renal I/R. The purpose of the present study is to investigate whether activation of autophagy prevents downregulation of AQP1 protein induced by renal I/R and potential molecular mechanisms. Renal I/R induced consistently reduced protein expression of AQP1, 2, and 3, as well as sodium cotransporters Na+-K+-2Cl(-) cotransporter and alpha-Na,K-ATPase, which was associated with increased urine output and decreased creatinine clearance in rats. Renal I/R also suppressed autophagy and increased inflammatory responses in the kidney. 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-di one (TDZD-8), the glycogen synthase kinase-3 beta inhibitor, ameliorated renal injury under I/R, activated autophagy and markedly increased expression of AQPs and sodium transporters in the kidney, which was associated with improved urine output and creatinine clearance in rats. Hypoxia/reoxygenation (H/R) induced suppression of autophagy and downregulation of AQP1 in murine inner medullary collecting duct 3 (IMCD3) cells, which was fully prevented by TDZD-8 treatment. Inhibition of autophagy by 3-methyladenine or Atg5 gene knockdown attenuated recovery of AQP1 protein expression induced by TDZD-8 in IMCD3 cells with H/R. Interleukin-1 beta (IL-1 beta) decreased the abundance of AQP1 protein in IMCD3 cells. H/R induced increases in protein expression of nod-like receptor pyrin domain-containing 3 and IL-1 beta, which was reversed by TDZD-8. In conclusion, TDZD-8 treatment prevented downregulation of AQP1 expression under renal I/R injury, likely via activating autophagy and decreasing IL-1 beta production.