Inhibition of mTOR protects against skeletal muscle and kidney injury following hindlimb ischemia-reperfusion in rats by regulating MEK1/ERK1/2 activity

Purpose: We have previously demonstrated that activation of the mammalian target of rapamycin (mTOR)/inhibitory-xB-alpha/nuclear factor-xB p65 signaling pathway mediates organ injuries through increased oxidative/nitrosative stress and inflammatory response in rat models of hind limb ischemia/reperfusion (HL I/R). Following up our previous findings regarding I/R injury through mammalian target of rapamycin (mTOR), we aimed to focus on the possible interaction between mammalian target of rapamycin (mTOR and mitogen-activated protein kinase kinase (MEK)1/extracellular signal-regulated kinase (ERK) 1/2 pathway in hind limb ischemia/reperfusion (HL I/R) resulting in target and remote organ injuries in the present study. Materials and Methods: Male Wistar rats were divided into four groups. HL I/R was induced by occluding with tourniquets of both hind limbs. Following 4 h, the tourniquets were removed following reperfusion for 4 h. After 4 h of reperfusion blood, kidney, and gastrocnemius muscle were collected. Results: HL I/R caused an increase in phosphorylation and/or expression of rpS6, MEK1, ERK1/2, tumor necrosis factor-alpha, inducible nitric oxide synthase, gp91(phox), p22(phox), and nitrotyrosine as well as nitrite levels in gastrocnemius muscle, kidney, and/or serum. Additionally, nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase levels were increased in the tissues of rats subjected to HL I/R. Rapamycin, the selective inhibitor of mTOR, abolished all the effects mentioned above caused by HL I/R in the rat's muscle and kidney. Conclusion: These data suggest that activation of the MEK1/ERK1/2 pathway contributes to mTOR-mediated HL I/R-induced target and remote organ injury.