Ischemia-reperfusion injury in renal transplantation: 3 key signaling pathways in tubular epithelial cells

Abstract

Renal ischemia-reperfusion injury (IRI) is a significant clinical challenge faced by clinicians perioperatively in kidney transplantation. Recent work has demonstrated the key importance of transmembrane receptors in the injured tubular epithelial cell, most notably Toll-like receptors, activated by exogenous and endogenous ligands in response to external and internal stresses. Through sequential protein-protein interactions, the signal is relayed deep into the core physiological machinery of the cell, having numerous effects from upregulation of proinflammatory gene products through to modulating mitochondrial respiration. Inter-pathway cross talk facilitates a co-ordinated response at an individual cellular level, as well as modulating the surrounding tissue's microenvironment through close interactions with the endothelium and circulating leukocytes. Defining the underlying cellular cascades involved in IRI will assist the identification of novel interventional targets to attenuate IRI with the potential to improve transplantation outcomes. We present a focused review of 3 key cellular signalling pathways in the injured tubular epithelial cell that have been the focus of much research over the past 2 decades: toll-like receptors, sphingosine-1-phosphate receptors and hypoxia inducible factors. We provide a unique perspective on the potential clinical translations of this recent work in the transplant setting. This is particularly timely with the recent completion of phase I and ongoing phase 2 clinical trials of inhibitors targeting specific components of these signaling cascades.

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

“…Ischemia/reperfusion (I/R) is a common complication in patients undergoing major cardiac surgery, kidney transplantation, and those experiencing hemorrhage and dehydration [1]. Ischemia/reperfusion injury (I/RI) after renal transplantation is a well-recognized and prevalent postoperative complication, which has been thought as a risk factor for the loss of tubular epithelial cell function, leading to acute kidney injury (AKI), delayed graft function, as well as acute or chronic organ rejection [2,3]. The process of renal ischemia reperfusion (RIR) is exceedingly complex, including a series of intricate and related events that lead to renal cell injury and ultimately give rise to cell death via apoptosis and necrosis [4].…”

Protection of the transplant kidney during cold perfusion with doxycycline: proteomic analysis in a rat model

“…Even with machine cold perfusion, significant preservation injury nonetheless occurs, and likely contributes to delayed graft function (DGF) and acute tubular necrosis in the transplanted kidney [21]. Injury of any cause is suspected to lead to a decrease in kidney function, shortened graft survival, and an increase in rejection due to increased activation of the immune system [4,22,23].…”

Kidney Perfusion as an Organ Quality Assessment Tool—Are We Counting Our Chickens Before They Have Hatched?

“…These signalling molecules are produced by leukocytes and endothelial cells. Injury to tubular epithelial cells has also been shown to influence upregulation of cytokines and chemokines by means of three key cellular pathways [133]. Damage associated patterns (DAMP's), like high-mobility group box-1 (HMGB-1), are endogenous ligands binding to Toll like receptors (TLR), resulting in activated cellular pathways with production of proinflammatory cytokines and chemokines [131,132].…”

“…Damage associated patterns (DAMP's), like high-mobility group box-1 (HMGB-1), are endogenous ligands binding to Toll like receptors (TLR), resulting in activated cellular pathways with production of proinflammatory cytokines and chemokines [131,132]. TLR-activated pathways also interact with the complement system [133]. Additionally, sphingosine-1-phosphate, produced by endothelial cells, platelets, and leukocytes, binds to G-protein-coupled receptors on tubular epithelial cells which can affect mitochondrial structure and function and can mediate proapoptotic and proinflammatory effects [133].…”

“…TLR-activated pathways also interact with the complement system [133]. Additionally, sphingosine-1-phosphate, produced by endothelial cells, platelets, and leukocytes, binds to G-protein-coupled receptors on tubular epithelial cells which can affect mitochondrial structure and function and can mediate proapoptotic and proinflammatory effects [133]. Finally, hypoxia inducible factors are known to induce glycolytic metabolism and to regulate production of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) [131,133].…”