Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation

Abstract

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.

Keywords: anesthesiology; anesthetic conditioning; ischemia reperfusion injury; kidney transplantation; organ protection; volatile anesthetics.

Figure 1

Potential protective points of engagement of volatile anesthetics (VA) in ischemia reperfusion injury (IRI). ATP: adenosine triphosphate; EndMT: endothelial to mesenchymal transition; HIF: hypoxic inducible factor; I/R: ischemia/reperfusion; LFA-1: lymphocyte function antigen-1; mPTP: mitochondrial permeability transition pore; ROS: reactive oxygen species.

Figure 2

Proposed effects of volatile anesthetics on the level of mitochondria. VA are likely to reduce complex III activity in the mitochondrial respiratory chain, resulting in an increase in superoxide (an ROS) formation. Superoxide then may react with nitric oxide, resulting in the formation of peroxynitrite, which itself reduces electron transport at complex I leading to more superoxide formation. From here, several pathways can be induced, ultimately resulting in reduced formation of mPTP (via PKC) or the prevention of opening of mPTP (via RISK or SAFE pathways). NAD: nicotinamide–adenine–dinucleotide; FAD: flavin–adenine–dinucleotide; CL-Cyt C: cytochrome C oxidase; PKC-ε: protein kinase C-ε; Pi: phosphate; Ψm: membrane potential; mPTP: mitochondrial permeability transition pore; PI3K: phosphoinositol 3 kinase; MAPK: mitogen activated kinse; JAK: Janus kinase; AKT: protein kinase B; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; ERK1/2: extracellular signal-regulated kinases1/2; P70SK6: ribosomal protein S6 kinase beta-1; GSK3β: glycogen synthase kinase 3 beta; Bcl-2: B cell lymphoma 2; Bax: bcl-2-like protein 4; Bad: BCL2 associated agonist of cell death; RISK pathway: reperfusion injury salvage kinase; SAFE pathway: survivor activating factor enhancement pathway.

Figure 3

Proposed effect of volatile anesthetics on renal tubular cells and the sphingosine-1-phosphate signaling pathway. Exposure of renal tubular cells leads to the externalization of phosphatidylserine (PS) with a release of transforming growth factor-β (TGF-β) and the formation of caveolae with sequestration of key signaling proteins such as TGF-β receptors, extracellular regulated kinase (ERK), sphingosine kinase 1 (SK-1) and sphingosine-1-phosphate (S1P). SMAD-3: mothers against decapentaplegic homolog 3; CD: cluster of differentiation; HIF-α: hypoxic inducible factor-α; A1AR: A1 adenosine receptor; IL-11: interleukin 11; IL-11R: IL-11 receptor. Adapted from: Fukazawa K, Lee HT. Volatile anesthetics and AKI: risks, mechanisms, and a potential therapeutic window. J. Am. Soc. Nephrol. 2014 May; 25(5):884–892. doi:10.1681/ASN.2013111215.

Figure 4

Interaction of LFA-1 with its ligands and consequences. Upon activation of the leukocyte by chemokines or antigens, lymphocyte function antigen-1 (LFA-1) undergoes conformational changes, facilitating its ability to bind with its ligand, via a process which is called inside-out signaling. The most important ligand for LFA-1 is intercellular adhesion molecule 1 (ICAM-1), of which expression on endothelial cells, antigen presenting cells (APCs) and other cells is increased upon IRI. Interaction of LFA-1 with endothelial ICAM-1 assures firm adhesion of the leukocyte to the endothelial cells and facilitates transmigration of the leukocyte into the interstitium. In the case of natural killer (NK) cells, LFA-1–target cell ICAM-1 interaction is necessary for activation of the NK cell and lysis of the target cell. LFA-1 activation on T cells facilitates APC binding and is involved in T cell activation. VA are able to inhibit activation of LFA-1, keeping it in its folded state. MHC-II: major histocompatibility complex II; TCR: T cell receptor.