Novel signalling mechanisms and targets in renal ischaemia and reperfusion injury

Abstract

Acute kidney injury (AKI) induced by ischaemia and reperfusion (I/R) injury is a common and severe clinical problem. Vascular dysfunction, immune system activation and tubular epithelial cell injury contribute to functional and structural deterioration. The search for novel therapeutic interventions for I/R-induced AKI is a dynamic area of experimental research. Pharmacological targeting of injury mediators and corresponding intracellular signalling in endothelial cells, inflammatory cells and the injured tubular epithelium could provide new opportunities yet may also pose great translational challenge. Here, we focus on signalling mediators, their receptors and intracellular signalling pathways which bear potential to abrogate cellular processes involved in the pathogenesis of I/R-induced AKI. Sphingosine 1 phosphate (S1P) and its respective receptors, cytochrome P450 (CYP450)-dependent vasoactive eicosanoids, NF-κB- and protein kinase-C (PKC)-related pathways are representatives of such 'druggable' pleiotropic targets. For example, pharmacological agents targeting S1P and PKC isoforms are already in clinical use for treatment for autoimmune diseases and were previously subject of clinical trials in kidney transplantation where I/R-induced AKI occurs as a common complication. We summarize recent in vitro and in vivo experimental studies using pharmacological and genomic targeting and highlight some of the challenges to clinical application of these advances.

Effects of melatonin on the serum levels of pro-inflammatory cytokines and tissue injury after renal ischemia reperfusion in rats

“…4,5 Renal tubular epithelial cells, simultaneously targets, and mediators of IR injury express several pro-inflammatory and chemotactic cytokines such as monocyte chemoattractant protein 1 (MCP-1), IL-1b, IL-6, IL-8, TNF-a, and transforming growth factor beta (TGF-b) are expressed in acute kidney injury (AKI), a severe clinical problem induced by IR injury. 6 TNF-a has a major role in IR injury, occurred after liver, kidney, intestine, heart, lung, and pancreas transplantation. 7,8 The plasma concentrations of TNF-a-and IL-1 are increased after renal ischemia.…”

Aloperine Protects Mice against Ischemia-Reperfusion (IR)-Induced Renal Injury by Regulating PI3K/AKT/mTOR Signaling and AP-1 Activity

“…To address this fea sibility, we conducted studies in mice cells, leukocytes, and renal parenchymal cells (7)(8)(9)(10)(11). Particularly, interplay bet ween inflammatory cytokines/chemo kines, apoptotic factors and reactive oxygen species (ROS) has been observed during the course of IRinduced renal injury (12)(13)(14)(15). Because of this complex ity, its underlying molecular mechanisms remained poorly understood (16,17).…”

An RNA interference screen identifies new avenues for nephroprotection

“…It is clear that multiple processes contribute to cell death during AKI, and simultaneous targeting of multiple pathways may be needed for maximal protection. 13 To this end, we investigated whether interference with any of the confirmed mediators of ischemic death could further improve the peak protection, which is rendered by chemical inhibition of NK1R. Indeed, we observed that interference with C2ORF42 or RHOB consistently increased the maximal efficacy of the drugs (Figures 5a and b; Supplementary Figure 5).…”

“…16 Our effort was inspired by the observations that the death of hypoxic kidney cells is an active process, both in the sense of metabolic maladaptations that inflict the initial biochemical insult, and in the sense of mechanisms that recognize the damage and commit cellular pathways to cell death. 7,13,17 This suggests a possibility of nephroprotection via inhibition of certain cellular factors. RNA interference-based genetic approaches are well suited for discovering such factors.…”

“…12 The enormous public health significance has attracted considerable effort to the development of strategies to prevent or reduce the damage from ischemic AKI. 7,13 Current treatment options are aimed at controlling known risk factors in highly susceptible populations or at attempting to replace renal function in patients who have lost it due to injury.…”