Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 20, Issue 6, Pages 1527-1537Publisher
WILEY
DOI: 10.1111/ajt.15794
Keywords
fibrosis; graft survival; kidney (allograft) function; dysfunction; kidney transplantation; nephrology; kidney transplantation; living donor; translational research; science
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R44DK103389]
- Osaka Medical Foundation
- Biomedical Education Program (BMEP)
- German Academic Exchange Service
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Inflammatory responses associated with ischemia/reperfusion injury (IRI) play a central role in alloimmunity and transplant outcomes. A key event driving these inflammatory responses is the burst of reactive oxygen species (ROS), with hydrogen peroxide (H2O2) as the most abundant form that occurs as a result of surgical implantation of the donor organ. Here, we used a syngeneic rat renal transplant and IRI model to evaluate the therapeutic properties of APP-103, a polyoxalate-based copolymer molecule containing vanillyl alcohol (VA) that exhibits high sensitivity and specificity toward the production of H2O2. We show that APP-103 is safe, and that it effectively promotes kidney function following IRI and survival of renal transplants. APP-103 reduces tissue injury and IRI-associated inflammatory responses in models of both warm ischemia (kidney clamping) and prolonged cold ischemia (syngeneic renal transplant). Mechanistically, we demonstrate that APP-103 exerts protective effects by specifically targeting the production of ROS. Our data introduce APP-103 as a novel, nontoxic, and site-activating therapeutic approach that effectively ameliorates the consequences of IRI in solid organ transplantation.
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