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      Allopurinol in Renal Ischemia

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          Abstract

          Allopurinol is a xanthine oxidase inhibitor and antioxidant free radical scavenger which facilitates the protection of ischemic organs in part via this mechanism of action. The accumulation of free radicals during ischemia and reperfusion is in great manner overcome by inhibitors of xanthine oxidase and by the development of endogenous antioxidants. The ischemic lesion generates a well-established inflammatory response with the subsequent production of inflammatory molecules characteristically present at the first stages of the injury. Inflammatory cytokines, chemokines, adhesion molecules, and other cellular and molecular compounds are consequently produced as the lesion sets in. Under these conditions, allopurinol diminishes the effect of inflammatory mediators during the ischemic inflammatory response. This study reviews the literature associated with allopurinol and renal ischemia making special emphasis on the best dose and time of administration of allopurinol regarding its protective effect. It also defines the most accepted mechanism of protection on ischemichally damaged kidneys.

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          Most cited references69

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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 TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation

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              A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling.

              A conserved domain in the extracellular region of the 60- and 80-kilodalton tumor necrosis factor receptors (TNFRs) was identified that mediates specific ligand-independent assembly of receptor trimers. This pre-ligand-binding assembly domain (PLAD) is physically distinct from the domain that forms the major contacts with ligand, but is necessary and sufficient for the assembly of TNFR complexes that bind TNF-alpha and mediate signaling. Other members of the TNFR superfamily, including TRAIL receptor 1 and CD40, show similar homotypic association. Thus, TNFRs and related receptors appear to function as preformed complexes rather than as individual receptor subunits that oligomerize after ligand binding.
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                Author and article information

                Journal
                Journal of Investigative Surgery
                Journal of Investigative Surgery
                Informa UK Limited
                0894-1939
                1521-0553
                December 19 2013
                October 2014
                June 10 2014
                October 2014
                : 27
                : 5
                : 304-316
                Article
                10.3109/08941939.2014.911395
                24914485
                02236e02-a2b1-4e6d-8459-25a9bcc48777
                © 2014
                History

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