Abstract
Renal ischaemia reperfusion (I/R) triggers a cascade of events including oxidative stress, apoptotic body and microparticle (MP) formation as well as an acute inflammatory process that may contribute to organ failure. Macrophages are recruited to phagocytose cell debris and MPs. The tyrosine kinase receptor MerTK is a major player in the phagocytosis process. Experimental models of renal I/R events are of major importance for identifying I/R key players and for elaborating novel therapeutical approaches. A major aim of our study was to investigate possible involvement of MerTK in renal I/R. We performed our study on both natural mutant rats for MerTK (referred to as RCS) and on wild type rats referred to as WT. I/R was established by of bilateral clamping of the renal pedicles for 30′ followed by three days of reperfusion. Plasma samples were analysed for creatinine, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), kidney injury molecule -1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels and for MPs. Kidney tissue damage and CD68-positive cell requirement were analysed by histochemistry. monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and histone 3A (H3A) levels in kidney tissue lysates were analysed by western blotting. The phagocytic activity of blood-isolated monocytes collected from RCS or WT towards annexin-V positive bodies derived from cultured renal cell was assessed by fluorescence-activated single cell sorting (FACS) and confocal microscopy analyses. The renal I/R model for RCS rat described for the first time here paves the way for further investigations of MerTK-dependent events in renal tissue injury and repair mechanisms.
Highlights
Confirmed that RCS rats that were used in the present study, noted RCS hereafter, do not express a full functional MerTK protein
For each of the groups and subgroups defined in the methods section, the plasma levels of the following known biomarkers of renal I/R injury: Creatinine, Urea, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), kidney injury molecule -1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), were determined seven days before surgery (D-7, baseline level), on day 1 (D1), and on day 3 (D3) post-I/R
These results show that the absence of functional MerTK has little impact on the plasma expression of the monocyte chemoattractant protein-1 (MCP-1) chemoattractant marker or on the CD68-positive phagocytic cell recruitment in renal tissue or on the expression of activated macrophage/neutrophil markers
Summary
Dying cells may release damage-associated molecular patterns (DAMPs) that are mainly pro-inflammatory factors responsible for leukocyte recruitment as well as microparticle (MPs) [6,7]. At the site of tissue injury, neutrophils may release their. DNA contents that act as neutrophil extracellular traps (NET) and induce surrounding cell necrosis, enhancing the inflammatory process [8,9,10]. Macrophages, through reactions between Nitric Oxyde (NO) and Reactive Oxygen Species (ROS), release peroxnitrites, which are cytotoxic products that contribute to cell damage while recruited leukocytes by phagocytosing cellular debris contribute to the repair process [11,12,13,14]
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