AMP-Activated Protein Kinase as a Target for Preconditioning in Transplantation Medicine

Abstract

Graft quality before transplantation is a major factor influencing chronic rejection. Organ preservation and ischemia/reperfusion play an important role in the induction of organ injury. Although both suppression of metabolism by hypothermic preservation and preconditioning before ischemia limit injury, understanding the biochemical signaling pathways will allow us to optimize graft preservation further. Adenosine monophosphate-activated protein kinase (AMPK) is an important enzyme sensing cellular energy balance and regulating downstream signaling pathways, signaling toward an energy-conserving state. In this review, we summarize available literature regarding the protective signaling pathways activated by (hypothermic) ischemia and preconditioning and how they can be activated pharmacologically. Optimizing the graft quality before transplantation improves long-term graft survival. The major factor influencing organ quality is organ preservation, cold storage, currently, being a common practice. Loss of cellular homeostasis, inflammation, and endothelial dysfunction are the major factors inducing injury after cold storage. Adenosine triphosphate depletion and anaerobic metabolism during the cold ischemic period lead to mitochondrial dysfunction, disturbed osmoregulation, and cell death inducing inflammation. Ischemic preconditioning consists of brief periods of ischemia preceding preservation and protects organs against injury because of subsequent ischemia/reperfusion, in which endothelial nitric oxide synthase, nuclear factor-kB, and adenosine play a major role. After conversion of adenosine to AMP, AMPK can be activated, a central kinase involved in sensing cellular [AMP]:[adenosine triphosphate] levels and signaling toward an energy-conserving state. Pharmacologic activation of AMPK demonstrated its ability to activate endothelial nitric oxide synthase and inhibit nuclear factor-kB, thereby limiting endothelial dysfunction and inflammation. Further, studies in knock-out mice lacking ENTDP1 and NT5E (enzymes catalyzing formation and degradation of AMP, respectively) demonstrated a clear protective role for AMP in ischemia/reperfusion. AMPK activation before or during organ preservation might be a promising pharmacologic approach to limit organ injury and maintain graft quality before transplantation.

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

“…There was also a solution effect on cortical microcirculation after unclamping reflected by higher laser Doppler values in the MPS groups than in the UW groups. Further studies should evaluate the role of AMPKa in the solution effect on cortical microcirculation because AMPKa has been reported to play a role in the protective mechanisms of preservation solutions (45) and in the ischemic preconditioning of liver grafts (46).…”

Potential benefits of melatonin in organ transplantation: a review

“…Similar results were observed when CE and IGL1 were compared. Moreover, in partial grafts, IGL1 provided better survival than the other solutions because it increased the mediators that promote liver regeneration such as AMP-activated protein kinase (AMPK) (Bouma et al 2010). Furthermore, UW and IGL1 solutions enriched with trophic factors, such as epidermal growth factor and insulin-like growth factor-1, are observed to enhance the resistance of steatotic livers …”

Place de l’AMP-activated protein kinase dans le préconditionnement ischémique rénal

“…Notons que quasiment toutes les é tudes chez l'homme, enregistré es auprè s de l'agence Clinicaltrials.gov, s'inté ressent à la phase pré coce du PCI. Dans le domaine de la transplantation ré nale, le PCI pourrait être utilisé au moment du pré lè vement de l'organe afin de limiter les lé sions des cellules tubulaires ré nales et pré venir la mort des cellules endothé liales vasculaires [1,2]. Cependant, la ré alisation d'un PCI chirurgical au moment du pré lè vement d'un rein risquerait d'endommager les structures vasculaires.…”

“…In vivo, le dé mantè lement des JS et la perte de polarisation des cellules tubulaires repré sentent l'une des premiè res manifestations histologiques de souffrance isché mique ré nale [7]. Vu que l'AMPK est abondamment exprimé e dans diffé rents segments du né phron, il é tait tentant de postuler qu'une privation é nergé tique ré nale, telle que celle observé e lors d'une isché mie, s'accompagnerait d'une activation de l'AMPK, et que l'activation pharmacologique de l'AMPK avant un é pisode d'isché mie/reperfusion maintiendrait la distribution polarisé e des transporteurs membranaires dans les cellules tubulaires ré nales, atté nuerait le dommage isché mique, et participerait ainsi aux mé canismes de protection ré nale [2].…”

“…Cette co-morbidité augmente la sensibilité du greffon aux phé nomè nes d'I/R [1]. La recherche dans le domaine de la transplantation ré nale se focalise donc sur ces diffé rents aspects afin d'amé liorer les conditions de pré lè vement, de pré servation, d'allocation et de transplantation d'un greffon ré nal, et partant d'en allonger la survie [1,2]. In fine, ces travaux visent à pré parer l'organe avant sa transplantation et ainsi atté nuer les lé sions d'I/R.…”