Modulation of oxidative–nitrosative stress and inflammatory response by rapamycin in target and distant organs in rats exposed to hindlimb ischemia–reperfusion: the role of mammalian target of rapamycin

• Published in: Canadian journal of physiology and pharmacology 2019-12, Vol.97 (12), p.1193-1203
• Main Authors: Kocak, Zumrut, Temiz-Resitoglu, Meryem, Guden, Demet Sinem, Vezir, Ozden, Sucu, Nehir, Balcı, Senay, Tamer-Gumus, Lulufer, Tunctan, Bahar, Malik, Kafait U, Sahan-Firat, Seyhan
• Format: Article
• Language: English
• Subjects: Adenine; Animals; Antioxidants; Aprotinin; Biomarkers - metabolism; Catalase; COX-2 inhibitors; Cyclooxygenase-2; Effects; Ethylenediaminetetraacetic acid; Gastrocnemius muscle; Gene Expression Regulation, Enzymologic - drug effects; Hindlimb - blood supply; hindlimb ischemia–reperfusion; Immunomodulation; Inflammation; Inflammation - metabolism; Inflammatory response; Inhibitor drugs; Injuries; Ischemia; ischémie–reperfusion de la patte postérieure; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Male; Malondialdehyde; mTOR; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; NAD(P)H oxidase; NADPH-diaphorase; NF-KappaB Inhibitor alpha - metabolism; NF-κB protein; Niacinamide; Nicotinamide; Nitric oxide; Nitric-oxide synthase; Nitrosative Stress - drug effects; Nitrotyrosine; Organs; Oxidases; Oxidative stress; Oxidative Stress - drug effects; oxidative–nitrosative stress; Peroxidase; Pharmacology; Phosphates; Physiology; Rapamycin; Rats; Rats, Wistar; Reactive nitrogen species; Reactive oxygen species; Reperfusion; Reperfusion Injury - metabolism; Ribosomal protein S6; Ribosomal Protein S6 - metabolism; Rodents; rpS6; Signal transduction; Sirolimus - pharmacology; Stress; stress oxydatif–nitrosatif; Studies; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription Factor RelA - metabolism; Tumor necrosis factor-α
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2019-0394

Mammalian target of rapamycin (mTOR) has been recognized with potential immunomodulatory properties playing an important role in various physiopathological processes including ischemia–reperfusion (I/R) injury. I/R injury stimulate reactive oxygen and nitrogen species by activating nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase, respectively. Controversial results have been obtained in different I/R models following localized I/R; however, the precise role of the mTOR signaling pathway remains undefined. The objective of the current study was to evaluate the role of the mTOR in oxidative–nitrosative stress and inflammation in hindlimb I/R-induced injury in target and remote organ injuries. In rats subjected to I/R, an increased expression of ribosomal protein S6 (rpS6), inhibitor κB (IκB)-α, nuclear factor-κB (NF-κB) p65, inducible nitric oxide synthase, cyclooxygenase 2, gp91 phox , and levels of tumor necrosis factor α, nitrite, nitrotyrosine, malondialdehyde and the activities of myeloperoxidase and catalase in the tissues and (or) sera were detected. Treatment with rapamycin, a selective inhibitor of mTOR, reversed all the I/R-induced changes as manifested by its anti-inflammatory and antioxidant effects in kidney and gastrocnemius muscle of rats. Collectively, these findings suggest that rapamycin protects against I/R-induced oxidative–nitrosative stress and inflammation leading to organ injuries via suppression of mTOR/IκB-α/NF-κB signaling pathway.