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      The anticoagulants ASIS or APC do not protect against renal ischemia/reperfusion injury

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          Abstract

          Renal ischemia/reperfusion (I/R) injury is the main cause of acute renal failure. The severity of injury is determined by endothelial damage as well as inflammatory and apoptotic processes. The anticoagulants active site inhibited factor VIIa (ASIS) and activated protein C (APC) are besides their anticoagulant function also known for their cytoprotective properties. In this study the effect of ASIS and APC was assessed on renal I/R injury and this in relation to inflammation and apoptosis. Our results showed no effect of ASIS or APC on renal injury as determined by histopathological scoring as well as by blood urea nitrogen (BUN) and creatinine levels. Furthermore, no effect on fibrin staining was detected but ASIS did reduce tissue factor activity levels after a 2-hr reperfusion period. Neither ASIS nor APC administration influenced overall inflammation markers, although some inflammatory effects of ASIS on interleukin (IL)-1β and tumor necrosis factor (TNF)-α were detectable after 2 hr of reperfusion. Finally, neither APC nor ASIS had an influence on cell signaling pathways or on the number of apoptotic cells within the kidneys. From this study we can conclude that the anticoagulants ASIS and APC do not have protective effects in renal I/R injury in the experimental setup as used in this study which is in contrast to the protective effects of these anticoagulants in other models of I/R.

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          Most cited references 34

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          TLR4 activation mediates kidney ischemia/reperfusion injury.

          Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4(-/-) and MyD88(-/-) mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4(-/-) and MyD88(-/-) TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4(-/-) mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4(-/-) BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage.
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            The cytoprotective protein C pathway.

            Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.
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              Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.

              Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.
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                Author and article information

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                Journal
                SOR-MED
                ScienceOpen Research
                ScienceOpen
                2199-1006
                12 June 2014
                : 0 (ID: 34421699-3b09-497d-bf20-61b35dfb919f )
                : 0
                : 1-10
                Affiliations
                [1 ]Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center+, Maastricht, The Netherlands
                [2 ]Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
                [3 ]Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center+, Maastricht, The Netherlands
                [4 ]Department of General Surgery, School for Nutrition & Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, The Netherlands
                [5 ]Department of Pathology, Maastricht University Medical Center+, Maastricht, The Netherlands
                Author notes
                [* ]Corresponding author's e-mail address: henri.spronk@ 123456maastrichtuniversity.nl
                Article
                3754:XE
                10.14293/S2199-1006.1.SOR-MED.AYXBIK.v1
                © 2014 S.T.B.G. Loubele et al.

                This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

                Page count
                Figures: 6, Tables: 2, References: 36, Pages: 10
                Product
                Categories
                Original Article

                Internal medicine

                apoptosis, renal ischemia/reperfusion, anti-coagulants, inflammation

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