Vectisol Formulation Enhances Solubility of Resveratrol and Brings Its Benefits to Kidney Transplantation in a Preclinical Porcine Model

Abstract

Current organ shortages have led centers to extend the acceptance criteria for organs, increasing the risk for adverse outcomes. Current preservation protocols have not been adapted so as to efficiently protect these organs. Herein, we target oxidative stress, the key mechanism of ischemia reperfusion injury. Vectisol® is a novel antioxidant strategy based on the encapsulation of resveratrol into a cyclodextrin, increasing its bioavailability. We tested this compound as an additive to the most popular static preservation solutions and machine perfusion (LifePort) in a preclinical pig model of kidney autotransplantation. In regard to static preservation, supplementation improved glomerular filtration and proximal tubular function early recovery. Extended follow-up confirmed the higher level of protection, slowing chronic loss of function (creatininemia and proteinuria) and the onset of histological lesions. Regarding machine perfusion, the use of Vectisol® decreased oxidative stress and apoptosis at the onset of reperfusion (30 min post declamping). Improved quality was confirmed with decreased early levels of circulating SOD (Superoxide Dismutase) and ASAT (asparagine amino transferase). Supplementation slowed the onset of chronic loss of function, as well as interstitial fibrosis and tubular atrophy. The simple addition of Vectisol® to the preservation solution significantly improved the performance of organ preservation, with long-term effects on the outcome. This strategy is thus a key player for future multi-drug therapy aimed at ischemia reperfusion in transplantation.

Effects of resveratrol on the inflammatory response and renal injury in hyperuricemic rats

“…Resveratrol also has been shown to activate manganese SOD in renal proximal tubule cells (NRK52E), thus protecting against nicotine-induced oxidative injury [ 30 ]. Moreover, supplementation of resveratrol improved glomerular filtration as well as decreased proteinuria, oxidative stress, and the levels of circulating SOD in a pig model of kidney autotransplantation [ 31 ]. Furthermore, the higher kidney tissue levels of MDA and the lower levels of reduced glutathione and activities of glutathione peroxidase and superoxide dismutase were reversed by resveratrol treatment [ 32 ].…”

Oxidative Stress Evaluation in Ischemia Reperfusion Models: Characteristics, Limits and Perspectives

“…In addition, some factors are amphiphilic and can act in either polar or non-polar environments. Table 1 lists and comments on the main chemical antioxidant systems [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

“…This strategy has been tested in our laboratory with tannic acid, which protects from IRI [ 25 ]. Other vectors or an osmotic pump facilitate the delivery and prolongation of the effect over several days [ 26 , 27 ].…”

“…Several studies have shown the protective potential of anti-oxidative therapeutics for IR injury [ 26 , 42 ]. However, OS is only one aspect of IR, especially in the context of organ transplantation.…”

New Insights in Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury 2.0: An Updated Overview

“…Several MP investigations in kidney have shown the benefits of incorporating antioxidants, such as Vectisol, which decreases the early levels of the detrimental radical oxygen species (ROS) [28] or mesenchymal cells, opening a new window to administer cell therapy to damaged organs [29] through MP in different preclinical transplantation models. These promising MP perspectives in kidney [28][29][30] have been extended to liver by using HOPE to rescue vulnerable livers, such as the ones from donors after cardiac death (DCD) and steatotic ones [24,25]. In this sense, the recent investigations by Schlegel et al [23] have established the protection mechanisms of HOPE based on the metabolism of succinate.…”