Nano-Self-Assembled Particles Loaded with Aldehyde Dehydrogenase 2 Agonist Inhibit Ischemia-Reperfusion Injury of
Qianchao Hu1, Zhongshan Lu1, Kalibinuer Yasen1
1Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, Wuhan 430071, China.
Abstract:
Kidney transplantation serves as an ideal treatment for patients with end-stage renal disease. Due to the organ shortage, there has been an uptick in the use of circulatory death donors (DCD), yet DCD kidneys endure severe ischemia-reperfusion injury (IRI), limiting transplantation efficacy. Therefore, we developed a strategy combining hypothermic machine perfusion (HMP) with aldehyde dehydrogenase 2 (ALDH2) agonist Alda-1, using quaternized chitosan/5β-cholanic acid/Alda-1 nanoparticles (A-NCH) for ex vivo DCD kidney repair. Methodologically, A-NCH was synthesized by conjugating O-hydroxypropyl trimethylammonium chloride chitosan (O-HTCC) with 5β-cholanic acid via EDC/NHS-mediated coupling, forming self-assembled micelles with a mean diameter of 132.4 ± 0.3 nm and ζ-potential of 45.0 ± 1.0 mV. It exhibited a high drug loading ratio (41.9%), with 80% of Alda-1 released at 4 °C within 3.5 h following the Weibull model, enabling sustained drug delivery during HMP. A-NCH demonstrated outstanding compatibility with cells and blood, as well as effective antibacterial properties combat Escherichia coli and Staphylococcus aureus. In vitro, A-NCH reduced H2O2- and oxygen-glucose deprivation- and -reoxygenation-induced oxidative stress and apoptosis in HK-2 and HUVECs. In vivo, using a rat DCD kidney transplantation model, A-NCH-administered HMP accelerated kidney graft function recovery and alleviated renal tubular injury. Mechanistically, A-NCH activated ALDH2, inhibited the P38 MAPK pathway, promoted nuclear translocation of TEAD4/YAP1, and suppressed the transition of proximal tubule cells to an injured phenotype. In this study, the solubility and drug loading of Alda-1 were improved by 5β-cholanic acid modification of O-HTCC, which proved the synergistic efficacy with HMP in DCD kidney repair and provided a translatable strategy to expand the donor pool.
Insights
This study introduces novel nanoparticles (A-NCH) that improve hypothermic machine perfusion (HMP) for repairing donated kidneys from circulatory death donors (DCD). This strategy enhances kidney graft function and recovery, potentially expanding the donor pool.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Transplantation Immunology
Background:
- Kidney transplantation is crucial for end-stage renal disease, but donor organ shortage is a major limitation.
- Donated kidneys from circulatory death donors (DCD) often suffer severe ischemia-reperfusion injury (IRI), compromising transplant outcomes.
- Developing strategies to repair DCD kidneys ex vivo is essential to improve transplantation efficacy and expand the donor pool.
Purpose of the Study:
- To develop and evaluate a novel nanoparticle system (A-NCH) for ex vivo DCD kidney repair.
- To investigate the synergistic effect of A-NCH with hypothermic machine perfusion (HMP) in improving DCD kidney quality.
- To elucidate the underlying mechanisms of A-NCH in mitigating IRI and promoting kidney graft recovery.
Main Methods:
- Synthesis of quaternized chitosan/5β-cholanic acid/Alda-1 nanoparticles (A-NCH) for sustained Alda-1 delivery during HMP.
- In vitro assessment of A-NCH biocompatibility, antibacterial properties, and protective effects against oxidative stress and apoptosis.
- In vivo evaluation of A-NCH-enhanced HMP in a rat DCD kidney transplantation model.
Main Results:
- A-NCH nanoparticles demonstrated optimal size, high drug loading, and sustained release of Alda-1 at 4°C.
- In vitro studies showed A-NCH reduced oxidative stress and apoptosis in kidney and endothelial cells.
- In vivo, A-NCH treatment significantly accelerated kidney graft function recovery and reduced tubular injury in DCD rat models.
- A-NCH activated ALDH2, inhibited P38 MAPK, and promoted TEAD4/YAP1 nuclear translocation, protecting against proximal tubule cell injury.
Conclusions:
- The developed A-NCH nanoparticles effectively improve Alda-1 solubility and loading for ex vivo DCD kidney repair.
- Combining A-NCH with HMP demonstrates synergistic efficacy in mitigating IRI and enhancing kidney graft function.
- This strategy offers a translatable approach to improve DCD kidney utilization and expand the donor organ pool.
