Aldehyde dehydrogenase 2 regulates autophagy via the Akt-mTOR pathway to mitigate renal ischemia-reperfusion injury in hypothermic machine perfusion

Lin, Danni; Tang, Xiang; Qiu, Qiangmin; Leung, Junto; Xu, Junjie; Wei, Zhou; Hu, Qianchao; Lan, Jianan; Liu, Zhongzhong; Zhong, Zibiao; Wang, Yanfeng; Ye, Qifa

doi:10.1016/j.lfs.2020.117705

Cited by 21 publications

(12 citation statements)

References 41 publications

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“…The MP benefits of ALDH2 extend further, as demonstrated by Lin et al [ 78 ], who evidenced that ALDH2 regulated autophagy via the Akt/mTOR pathway to mitigate renal ischemia–reperfusion injury and can activate the negative regulatory mammalian target of rapamycin (mTOR) pathway. We established similar protective autophagic mechanisms when IGL-2 and IGL-1 solutions were used [ 38 , 79 ].…”

Section: Some Considerations and Concluding Remarksmentioning

confidence: 85%

“…Recently, aldehyde dehydrogenase-2 has been described as a regulator of mitochondrial machinery during hypothermic machine perfusion to mitigate the deleterious effects of renal ischemia–reperfusion [ 78 ]. ALDH2 plays an important cytoprotective role in HMP, reducing the accumulation of 4-HNE and regulating the Akt/mTOR autophagy pathway in a similar way as in cold static preservation [ 79 ].…”

Section: Hope Mitochondrial and Glycocalyx Protection And Peg35 Efflu...mentioning

confidence: 99%

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Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads

Bardallo

Silva

Carbonell

et al. 2022

IJMS

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Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia–reperfusion injury that occurs in the complex route of the graft from “harvest to revascularization”. Recently, several preservation methods have been developed to preserve liver grafts based on hypothermic static preservation and hypothermic oxygenated perfusion (HOPE) strategies, either combined or alone. However, their effects on mitochondrial functions and their relevance have not yet been fully investigated, especially if different preservation solutions/effluents are used. Ischemic liver graft damage is caused by oxygen deprivation conditions during cold storage that provoke alterations in mitochondrial integrity and function and energy metabolism breakdown. This review deals with the relevance of mitochondrial machinery in cold static preservation and how the mitochondrial respiration function through the accumulation of succinate at the end of cold ischemia is modulated by different preservation solutions such as IGL-2, HTK, and UW (gold-standard reference). IGL-2 increases mitochondrial integrity and function (ALDH2) when compared to UW and HTK. This mitochondrial protection by IGL-2 also extends to protective HOPE strategies when used as an effluent instead of Belzer MP. The transient oxygenation in HOPE sustains the mitochondrial machinery at basal levels and prevents, in part, the accumulation of energy metabolites such as succinate in contrast to those that occur in cold static preservation conditions. Additionally, several additives for combating oxygen deprivation and graft energy metabolism breakdown during hypothermic static preservation such as oxygen carriers, ozone, AMPK inducers, and mitochondrial UCP2 inhibitors, and whether they are or not to be combined with HOPE, are presented and discussed. Finally, we affirm that IGL-2 solution is suitable for protecting graft mitochondrial machinery and simplifying the complex logistics in clinical transplantation where traditional (static preservation) and innovative (HOPE) strategies may be combined. New mitochondrial markers are presented and discussed. The final goal is to take advantage of marginal livers to increase the pool of suitable organs and thereby shorten patient waiting lists at transplantation clinics.

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Section: Some Considerations and Concluding Remarksmentioning

confidence: 85%

Section: Hope Mitochondrial and Glycocalyx Protection And Peg35 Efflu...mentioning

confidence: 99%

Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads

Bardallo

Silva

Carbonell

et al. 2022

IJMS

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“…Recently, one study demonstrated for the first time that Alda-1 treatment alleviated intestinal IR injury through the inhibition of oxidative stress, inflammatory response, and cell apoptosis ( 13 ). Two other studies demonstrated that ALDH2 overexpression mitigated IR-induced acute kidney injury by regulating cell autophagy via the beclin-1 pathway, and its activation by Alda-1 treatment alleviated renal IR injury in hypothermic machine perfusion through the Akt-mTOR autophagy signaling pathway ( 12 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Alda-1, a specific activator of aldehyde dehydrogenase 2 (ALDH2), has been shown to protect several target organs against regional IR injury through enhancing ALDH2-mediated detoxification of reactive aldehydes ( 11 ). Especially, two studies have manifested that the activation of ALDH2 by Alda-1 treatment is beneficial to mitigate renal and intestinal injuries in those regional IR models ( 12 , 13 ). In the setting of CA and resuscitation, another two studies have also confirmed that Alda-1 treatment is an effective therapeutic intervention for improving post-resuscitation myocardial dysfunction ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Alda-1 Treatment on Renal and Intestinal Injuries After Cardiopulmonary Resuscitation in Pigs

Gao

Shao

et al. 2022

Front. Med.

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AimAfter successful cardiopulmonary resuscitation (CPR), most survivors will develop acute kidney injury and intestinal barrier dysfunction, both of which contribute to the poor outcomes of cardiac arrest (CA) victims. Recently, the aldehyde dehydrogenase 2 (ALDH2) agonist, Alda-1 was shown to effectively alleviate regional ischemia/reperfusion injury of various organs. In the present study, we investigated the effects of Alda-1 treatment on renal and intestinal injuries after CA and resuscitation in pigs.MethodsTwenty-four male domestic pigs were randomly divided into one of the three groups: sham (n = 6), CPR (n = 10), or CPR+Alda-1 (n = 8). CA was induced and untreated for 8 min, and then CPR was performed for 8 min in the CPR and CPR+Alda-1 groups. At 5 min after resuscitation, a dose of 0.88 mg/kg of Alda-1 was intravenously administered in the CPR+Alda-1 group. The biomarkers of renal and intestinal injuries after resuscitation were regularly measured for a total of 24 h. Subsequently, the animals were euthanized, and then renal and intestinal tissues were obtained for the measurements of ALDH2 activity and expression, and cell apoptosis and ferroptosis.ResultsFive of the 10 animals in the CPR group and six of the eight animals in the CPR+Alda-1 group were successfully resuscitated. After resuscitation, the levels of biomarkers of renal and intestinal injuries were significantly increased in all animals experiencing CA and resuscitation compared with the sham group; however, Alda-1 treatment significantly alleviated renal and intestinal injuries compared to the CPR group. Post-resuscitation ALDH2 activity was significantly decreased and its expression was markedly reduced in the kidney and intestine in those resuscitated animals compared with the sham group; nevertheless, both of them were significantly greater in those animals receiving Alda-1 treatment compared to the CPR group. In addition, renal, intestinal apoptosis and ferroptosis after resuscitation were observed in the CPR and CPR+Alda-1 groups, in which both of them were significantly milder in the CPR+Alda1 group than in the CPR group.ConclusionsThe activation of ALDH2 by Alda-1 treatment significantly alleviated post-resuscitation renal and intestinal injuries through the inhibition of cell apoptosis and ferroptosis in a pig model of CA and resuscitation.

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“…Cold perfusion can provide sufficient time and an appropriate operating environment for autologous kidney transplantation. Hypothermic perfusion fluid can protect renal function during renal ischemia ( Lin et al, 2020 ), but one disadvantage of this method of continuous perfusion is that the effect is not accurate, and cell necrosis, apoptosis, and acute tubular necrosis are caused by blood supply recovery, especially when blood vessel anastomosis cannot be carried out ( Urbanellis et al, 2020 ). The common method is adding ice water during suture, but continuous insertion of ice slush in the abdominal cavity not only distracts the surgeon and increases operative time but also is a rudimental method that does not guarantee a homogeneous parenchymal cooling effect with the possibility of compromising graft function.…”

Section: Introductionmentioning

confidence: 99%

3D-Printed Cold Preservation Device in Renal Autotransplantation for the Treatment of a Patient With Renal Artery Stenosis

Dong

Da-li

et al. 2022

Front. Bioeng. Biotechnol.

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Percutaneous transluminal angioplasty (PTRA) is a common treatment method for renal vascular disease (RVD). However, PTRA may not be effective in patients with abnormal vascular disease. Renal autotransplantation (RAT) has been used as an alternative therapy for these diseases. Restrictions due to intracorporeal kidney cold preservation and the renal function of intracorporeal RAT were not as well protected compared with open operation. We developed this technique of 3D-printed polylactide (PLA) cold jackets for laparoscopic complete intracorporeal RAT for the purpose of better protecting the renal function and determining the feasibility of this novel procedure. The procedure was successfully applied to a 51-year-old woman with bilateral renal artery stenosis. The operation time was 5 hours, and blood loss was 200 ml. The patient’s blood pressure remained constant throughout the operation, and the pressure was maintained at 120-140/70–90 mmHg without antihypertensive drugs 1 week after the operation. B-ultrasound showed that the blood flow signal of the transplanted kidney was normal and the boundary between the skin and medulla was clear. The patient was discharged 2 weeks after surgery. One year postoperatively, Doppler ultrasound of the autotransplant showed that the transplanted kidney was normal in size and shape. Radionuclide renal dynamic imaging revealed that the glomerular filtration rate (GFR) of the transplanted kidney was 36.9 ml/min. 3D-printed polylactide (PLA) cold jackets for laparoscopic complete intracorporeal RAT are a safe and effective method for the treatment of renal artery stenosis and represent a feasible method for preserving the renal function of severe renal artery stenosis patients; however, the technology is still at the exploratory stage and has room for further improvements.

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Aldehyde dehydrogenase 2 regulates autophagy via the Akt-mTOR pathway to mitigate renal ischemia-reperfusion injury in hypothermic machine perfusion

Cited by 21 publications

References 41 publications

Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads

Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads

The Effects of Alda-1 Treatment on Renal and Intestinal Injuries After Cardiopulmonary Resuscitation in Pigs

3D-Printed Cold Preservation Device in Renal Autotransplantation for the Treatment of a Patient With Renal Artery Stenosis

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