Novel signalling mechanisms and targets in renal ischaemia and reperfusion injury

• Published in: Acta Physiologica Vol. 208; no. 1; pp. 25 - 40
• Main Authors: Kusch, A., Hoff, U., Bubalo, G., Zhu, Y., Fechner, M., Schmidt-Ullrich, R., Marko, L., Müller, D. N., Schmidt-Ott, K. M., Gürgen, D., Blum, M., Schunck, W.-H., Dragun, D.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2013; Wiley Subscription Services, Inc
• Subjects: Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - physiopathology; Acute Kidney Injury - therapy; Animals; Autoimmune diseases; Cells; Cytochrome P-450 Enzyme System - metabolism; eicosanoids; Eicosanoids - metabolism; Humans; ischaemia; Kidney - blood supply; Kidney - drug effects; Kidney - metabolism; kidney reperfusion injury; Kinases; Lysophospholipids - metabolism; Medical research; Molecular Targeted Therapy; NF-kappa B - metabolism; NFĸB; PKC; Prognosis; Protein Kinase C - metabolism; Proteins; Receptors, Lysosphingolipid - metabolism; Renal Circulation; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Reperfusion Injury - therapy; signal transduction; Signal Transduction - drug effects; Sphingosine - analogs & derivatives; Sphingosine - metabolism; sphingosine 1-P
• ISSN: 1748-1708; 1748-1716; 1748-1716
• DOI: 10.1111/apha.12089

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.