Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat
Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat
复制标题
DOI：
10.1093/ndt/gfm509
复制
发表时间：
2008-01-01
影响因子：
6.1
通讯作者：
Yu, Xueqing
中科院分区：
文献类型：
--
作者：
Yang, Niansheng;Luo, Mingqian;Yu, Xueqing
背景。JAK/STAT信号是细胞因子信号转导的主要途径之一。然而，JAK/STAT在肾缺血再灌注（I/R）损伤中的作用尚不清楚。本研究探讨了体内抑制JAK2激活对肾I/R损伤的保护作用。肾I/R大鼠每日腹腔注射选择性JAK2抑制剂tyrphostin AG490 (10mg/kg)，或在I/R前4小时、I/R后立即或I/R后3小时单独给药。观察大鼠肾功能、组织学、巨噬细胞浸润、细胞凋亡、趋化因子表达及粘附分子的变化。AG490处理显著抑制JAK2及其下游分子STAT1和STAT3的磷酸化。经AG490预处理的大鼠肾脏功能得到改善，肾小管上皮细胞凋亡减少，组织学病变减轻。AG490显著抑制肾脏MCP-1和ICAM-1 mRNA的表达以及ICAM-1蛋白的表达，并伴有肾脏巨噬细胞积聚减少。缺血后立即使用AG490治疗也能显著改善肾损伤。然而，延迟至I/R后3h的缺血后治疗未能减轻肾损害。本研究证实了JAK/STAT信号通路参与肾I/R损伤的发病机制，提示JAK/STAT通路可能作为缺血性急性肾功能衰竭早期干预的潜在靶点。
Background. JAK/STAT signalling is one of the major pathways for cytokine signal transduction. However, the role of JAK/STAT in renal ischaemia/reperfusion (I/R) injury is not clear. The present study investigated the protection against renal I/R injury by in vivo inhibition of JAK2 activation.Methods. Rats subjected to renal I/R were either treated with daily intraperitoneal injection of selective JAK2 inhibitor tyrphostin AG490 (10mg/kg) or vehicle alone starting 4h before, immediately after or until 3h after I/R. Renal function, histology, infiltration of macrophages, apoptosis, expression of chemokines and adhesion molecules were assessed.Results. AG490 treatment significantly inhibited the phosphorylation of JAK2 and its downstream molecule STAT1 and STAT3. Rats pretreated with AG490 exhibited improved renal function, attenuated histological lesions and reduced apoptosis of tubular epithelial cells. AG490 significantly inhibited renal expression of MCP-1 and ICAM-1 mRNA, as well as the expression of ICAM-1 protein, accompanied by decreased macrophage accumulation in the kidney. Immediate post-ischaemic treatment of AG490 also significantly ameliorated renal injury. However, delayed post-ischaemic treatment until 3h after I/R failed to attenuate renal damage.Conclusions. This study demonstrated the involvement of JAK/STAT signalling in the pathogenesis of renal I/R injury, suggesting that JAK/STAT pathway may serve as a potential target for early intervention in ischaemic acute renal failure.