Mitoquinone Alleviates Donation after Cardiac Death Kidney Injury during Hypothermic Machine Perfusion in Rat Model.
Anna RadajewskaJakub SzyllerAnna Krzywonos-ZawadzkaAgnieszka OlejnikGrzegorz SawickiIwona Bil-LulaPublished in: International journal of molecular sciences (2023)
Transplanted organs are subjected to harmful conditions through stopping blood flow, hypothermic storage of the graft, and subsequent reperfusion. In particular, kidneys donated from patients after cardiac arrest (DCD) are classified as more vulnerable to ischemia-reperfusion injury (IRI). Hypothermic machine perfusion is proposed as a solution for better kidney storage before transplantation, and it is a good platform for additional graft treatment. Antioxidants have gained interest in regenerative medicine due to their ability to scavenge reactive oxygen species (ROS), which play a key role in IRI. We evaluated the effect of Mitoquinone (MitoQ), a strong mitochondria-targeted antioxidant, administered directly to the perfusing buffer. Rat kidneys were isolated, randomly classified into one of the following groups, donation after brainstem death (DBD), DCD, and DCD with MitoQ, and perfused for 22 hours with a hypothermic machine perfusion system. Subsequently, we detected levels of kidney injury (KIM-1) and oxidative stress (ROS/RNS, cytochrome C oxidase, and mitochondrial integrity) markers. We compared the activation of the apoptosis pathway (caspase 3 and 9), the concentration of phosphorylated Akt (pAkt), and the pAkt/total Akt ratio. MitoQ reduces KIM-1 concentration, total ROS/RNS, and the level of caspases. We observed a decrease in pAkt and the pAkt/total Akt ratio after drug administration. The length of warm ischemia time negatively impacts the graft condition. However, MitoQ added to the perfusing system as an 'on pump' therapy mitigates injury to the kidney before transplantation by inhibiting apoptosis and reducing ROS/RNS levels. We propose MitoQ as a potential drug for DCD graft preconditioning.
Keyphrases
- oxidative stress
- reactive oxygen species
- ischemia reperfusion injury
- cell death
- dna damage
- blood flow
- signaling pathway
- induced apoptosis
- cardiac arrest
- diabetic rats
- end stage renal disease
- cell proliferation
- cell cycle arrest
- deep learning
- drug administration
- contrast enhanced
- ejection fraction
- chronic kidney disease
- peritoneal dialysis
- computed tomography
- newly diagnosed
- magnetic resonance imaging
- endoplasmic reticulum stress
- pi k akt
- emergency department
- coronary artery disease
- heat shock
- left ventricular
- cell therapy
- patient reported
- atrial fibrillation
- heat shock protein