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

Çağla Akıncı Uysal; Meryem Temiz Reşitoğlu; Demet Sinem Güden; Sefika Pınar Şenol; Özden Vezir; Nehir Sucu; Bahar Tunçtan; Kafait U. Malik; Seyhan Fırat

doi:10.17826/cumj.1021518

EN TR

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

Abstract

Purpose: We have previously demonstrated that activation of the mammalian target of rapamycin (mTOR)/inhibitory-κB-α/nuclear factor-κB 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-α, inducible nitric oxide synthase, gp91phox, p22phox, 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.

Keywords

mTOR , MEK1 , ERK1/2 , hind limb ischemia/reperfusion , oxidative/nitrosative stress , inflammation

mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar

Öz

Amaç: Arka bacak iskemisi/reperfüzyonun (İ/R) sıçan modellerinde, rapamisinin memelilerdeki hedefi (mTOR)/inhibitör-κB-α/nükleer faktör-κB p65 sinyal ileti yolu etkinliğinin, artan oksidatif/nitrozatif stres ve inflamatuvar yanıt yoluyla organ zedelenmelerine aracılık ettiğini daha önce göstermiştik. mTOR’un İ/R zedelenmesine katkıda bulunduğuna ilişkin önceki bulgularımızı referans alarak, bu çalışmada arka bacak İ/R'ye bağlı hedef ve uzak organ zedelenmelerinde mTOR ile MEK1/ERK1/2 yolu arasındaki olası etkileşime odaklanmayı amaçladık. Gereç ve Yöntem: Erkek Wistar sıçanlar dört gruba ayrıldı. Arka bacak İ/R, her iki arka ekstremitelerine turnikeler uygulanarak iskemi oluşturuldu. İskemiden 4 saat sonra turnikeler açılarak 4 saat reperfüzyon uygulandı. 4 saatlik reperfüzyondan sonra kan, böbrek ve gastroknemius kası izole edildi. Bulgular: Arka bacak İ/R uygulaması gastroknemius kasında, böbrekte ve/veya serumda rpS6, MEK1, ERK1/2, tümör nekroz faktörü-α, indüklenebilir nitrik oksit sentaz, gp91phox, p22phox ve nitrotirozinin fosforilasyonu ve/veya ekspresyonu ile birlikte nitrit düzeylerinde artışa neden oldu. Ayrıca, İ/R uygulanan sıçanların dokularında nikotinamit adenin dinükleotit fosfat oksidaz ve miyeloperoksidaz seviyeleri arttı. mTOR'un seçici inhibitörü olan rapamisin, sıçanlarda kas ve böbrek dokusunda İ/R'nin neden olduğu yukarıda bahsedilen tüm etkileri ortadan kaldırdı. Sonuç: Bu veriler, MEK1/ERK1/2 yolunun etkinliğinin, mTOR’un aracılık ettiği arka bacak İ/R’nin neden olduğu hedef ve uzak organ zedelenmesine katkıda bulunduğunu göstermektedir.

Anahtar Kelimeler

mTOR , MEK1 , ERK1/2 , arka bacak iskemi/reperfüzyon , oksidatif/nitrozatif stress , inflamasyon

Kaynakça

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Ayrıntılar

Birincil Dil

İngilizce

Konular

Klinik Tıp Bilimleri

Bölüm

Araştırma Makalesi

Yazarlar

Çağla Akıncı Uysal Bu kişi benim
0000-0002-4000-1054
Türkiye

Meryem Temiz Reşitoğlu
0000-0002-3326-2440
Türkiye

Demet Sinem Güden
0000-0001-5423-3641
Türkiye

Sefika Pınar Şenol
0000-0002-3019-9589
Türkiye

Özden Vezir
0000-0001-9948-0515
Türkiye

Nehir Sucu
0000-0002-7469-5883
Türkiye

Bahar Tunçtan Bu kişi benim
0000-0003-3439-7803
Türkiye

Kafait U. Malik Bu kişi benim
0000-0001-9157-0356
Türkiye

Seyhan Fırat ^*
0000-0002-8677-6381
Türkiye

Yayımlanma Tarihi

31 Mart 2022

Gönderilme Tarihi

17 Kasım 2021

Kabul Tarihi

24 Ocak 2022

Yayımlandığı Sayı

Yıl 1970 Cilt: 47 Sayı: 1

DOI

https://doi.org/10.17826/cumj.1021518

IZ

https://izlik.org/JA95ZR37JT

MLA

Akıncı Uysal, Çağla, vd. “Inhibition of mTOR protects against skeletal muscle and kidney injury following hindlimb ischemia-reperfusion in rats by regulating MEK1/ERK1/2 activity”. Cukurova Medical Journal, c. 47, sy 1, Mart 2022, ss. 219-32, doi:10.17826/cumj.1021518.

Bu eser Creative Commons Atıf-Gayriticari-Türetilemez 4.0 Uluslararası Lisansı ile lisanslanmıştır.

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

Abstract

Keywords

mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar

Öz

Anahtar Kelimeler

Kaynakça

Ayrıntılar

Birincil Dil

Konular

Bölüm

Yazarlar

Yayımlanma Tarihi

Gönderilme Tarihi

Kabul Tarihi

Yayımlandığı Sayı

DOI

IZ

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