Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat.
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 (10 mg/kg) or vehicle alone starting 4 h before, immediately after or until 3 h 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 3 h 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.
Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, PR China. zsuyns@163.com
Niansheng
N
Yang
Mingqian
M
Luo
Rong
R
Li
Yuefang
Y
Huang
Rui
R
Zhang
Qingqing
Q
Wu
Fang
F
Wang
Youji
Y
Li
Xueqing
X
Yu
D000818:Animals; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors*; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use*
D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507927:Jak2 protein, rat; D053614:Janus Kinase 2