Melatonin Modulates Endoplasmic Reticulum Stress and Akt/GSK3-Beta Signaling Pathway in a Rat Model of Renal Warm Ischemia Reperfusion

Tka, Kaouther Hadj Ayed; Boussaid, Asma Mahfoudh; Zaoualí, Mohamed Amine; Kammoun, Rim; Béjaoui, Mohamed; Ghoul-Mazgar, Sonia; Roselló‐Catafau, Joan; Abdennebi, Hassen Ben

doi:10.1155/2015/635172

Cited by 31 publications

(36 citation statements)

References 52 publications

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“…During I/R injury, misfolded or unfolded proteins accumulate in the ER lumen that leads to ER stress (Wang et al, ). Recently, studies described that renal I/R is associated with increased levels of GRP78, p‐PERK, ATF4, ATF6, XBP‐1, and CHOP (Hadj Ayed Tka et al, ; Mahfoudh‐Boussaid et al, ). In accordance with these data, our results demonstrated that renal I/R induced the elevation of the levels of GRP78, ATF‐6, p‐eIF‐2α, and XPB‐1.…”

Section: Discussionmentioning

confidence: 99%

Zinc mitigates renal ischemia‐reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy

Abdallah

Baulies

Bouhlel

et al. 2018

Journal Cellular Physiology

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Oxidative stress is a major factor involved in the pathogenesis of renal ischemia/reperfusion (I/R). Exogenous zinc (Zn) was suggested as a potent antioxidant; however, the mechanism by which it strengthens the organ resistance against the effects of reactive oxygen species (ROS) is not yet investigated. The present study aims to determine whether acute zinc chloride (ZnCl ) administration could attenuate endoplasmic reticulum (ER) stress, autophagy, and inflammation after renal I/R. Rats were subjected to either sham operation (Sham group, n = 6), or 1 hr of bilateral ischemia followed by 2 hr of reperfusion (I/R groups, n = 6), or they received ZnCl orally 24 hr and 30 min before ischemia (ZnCl group, n = 6). Rats were subjected to 1 hr of bilateral renal ischemia followed by 2 hr of reperfusion (I/R group, n = 6). Our results showed that ZnCl enhances renal function and reduces cytolysis (p < 0,05). In addition, it increased significantly the activities of antioxidant enzymes (SOD, CAT, and GPX) and the level of GSH in comparison to I/R (p < 0,05). Interestingly, ZnCl treatment resulted in significant decreased ER stress, as reflected by GRP78, ATF-6,p-eIF-2α, XPB-1, and CHOP downregulaion. Rats undergoing ZnCl treatment demonstrated a low expression of autophagy parameters (Beclin-1 and LAMP-2), which was correlated with low induction of apoptosis (caspase-9, caspase-3, and p-JNK), and reduction of inflammation (IL-1ß, IL-6, and MCP-1) (p < 0,05). In conclusion, we demonstrated the potential effect of Zn supplementation to modulate ER pathway and autophagic process after I/R.

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Section: Discussionmentioning

confidence: 99%

Zinc mitigates renal ischemia‐reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy

Abdallah

Baulies

Bouhlel

et al. 2018

Journal Cellular Physiology

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“…VDAC1 is a protein involved in the regulation of cell metabolism and mitochondrial apoptosis. Some studies have demonstrated that downregulated VDAC1 leads to prevention of mitochondrial permeability transition pore opening and cell apoptosis (34–37). We also found that CD47mAb treated recipients had significantly lower VDAC1 expression compared with IgG-treated control group in the syngeneic model.…”

Section: Discussionmentioning

confidence: 99%

CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation

Wang

Jia

et al. 2018

American Journal of Transplantation

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Modulation of nitric oxide activity through blockade of CD47 signaling has been shown to reduce ischemia-reperfusion injury (IRI) in various models of tissue ischemia. Here, we evaluate the potential effect of an antibody-mediated CD47 blockade in a syngeneic and an allogeneic DCD rat kidney transplant model. The donor organ was subjected to 1 hour of warm ischemia time after circulatory cessation, then flushed with a CD47 monoclonal antibody (CD47mAb) in the treatment group, or an isotype-matched immunoglobulin in the control group. We found that CD47mAb treatment improved survival rates in both models. Serum markers of renal injury were significantly decreased in the CD47mAb-treated group compared with the control group. Histologically the CD47mAb-treated group had significantly reduced scores of acute tubular injury and acute tubular necrosis. The expression of biomarkers related to mitochondrial stress and apoptosis also were significantly lower in the CD47mAb-treated groups. Overall, the protective effects of CD47 blockade were greater in the syngeneic model. Our data show that CD47mAb blockade decreased the IRI of DCD kidneys in rat transplant models. This therapy has the potential to improve DCD kidney transplant outcomes in the human setting.

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“…A phosphorylated GSK3β increase is also involved in the adaptive mechanisms of hepato-protection against I/R injury induced by ischemic preconditioning in the liver [18]. Moreover, it has been reported that modulation of Akt and its downstream targets GSK3β and VDAC could be used as a potential therapeutic strategy for protecting the kidney against I/R injury [24]. …”

Section: Discussionmentioning

confidence: 99%

GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

Zaoualí

Panisello

Lopez

et al. 2017

IJMS

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Abstract:We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia-reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention.

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Melatonin Modulates Endoplasmic Reticulum Stress and Akt/GSK3-Beta Signaling Pathway in a Rat Model of Renal Warm Ischemia Reperfusion

Cited by 31 publications

References 52 publications

Zinc mitigates renal ischemia‐reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy

Zinc mitigates renal ischemia‐reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy

CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation

GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

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