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dc.contributor.advisorHughes, Jeremy
dc.contributor.advisorKluth, David
dc.contributor.authorFerenbach, David Arthur
dc.date.accessioned2011-02-15T10:07:00Z
dc.date.available2011-02-15T10:07:00Z
dc.date.issued2010
dc.identifier.urihttp://hdl.handle.net/1842/4806
dc.description.abstractIschaemia/Reperfusion Injury (IRI) is the most common cause of acute kidney injury- a devastating clinical problem lacking any specific treatments to promote renal recovery. Macrophages (Mφ) are pleiotropic cells of the innate immune system, with roles spanning host defence, cytotoxicity, clearance of apoptotic cells and promotion of tissue repair. Mφ are also known to be important mediators of renal injury in other experimental models of renal disease including transplantation, obstruction and glomerulonephritis. This work sought to examine the role of Mφ in mediating renal IRI. Conditional renal Mφ and monocyte depletion prior to experimental IRI was achieved by administering diphtheria toxin to the CD11b-DTR transgenic animal. This had no impact on either renal function or structural injury. In contrast liposomal clodronate mediated Mφ depletion provided functional and structural protection from injury. Administration of exogenous apoptotic cells also protected renal function if delivered 24h prior to IRI. Immunodeficient SCID mice exhibited a protected injury phenotype after IRI, however derived no additional protection from the administration of either liposomal clodronate or i.v. apoptotic cells. These findings suggest that the protective phenotype must involve either lymphocyte populations or circulating antibody. Preliminary work demonstrates that SCID mice lack IgM natural antibody which deposits in the kidney in the first 30 minutes after IRI. It was also demonstrated that apoptotic cells bind IgM natural antibody present within the circulation. The potential for the key antioxidant enzyme Heme oxygenase-1 (HO-1) to protect renal function was also examined in aged mice using hemearginate (HA) - a potent HO-1 inducer. Echoing epidemiological studies in humans aged mice had increased susceptibility to IRI, whilst failing to induce medullary HO-1. The main site of medullary HO-1 induction by HA was in medullary Mφ, and the protective phenotype was abolished by Mφ ablation, implicating Mφ as the key mediators of HA induced protection in renal IRI. Final studies employed adenoviral transduction to overexpress HO-1 within bone marrow derived Mφ, leading to a modified phenotype with increased IL- 10 and phagocytosis, and reduced TNFα and NO production. When these were introduced in vivo after IRI renal function was improved, potentially due to accelerated clearance of renal platelet deposition.en
dc.contributor.sponsorKidney Research UKen
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionFerenbach DA, Nkejabega NCJ, McKay J, Marson L, Kluth DC and Hughes J. Aged mice fail to induce HO-1 and exhibit augmented injury in experimental acute kidney injury. Kidney Int.en
dc.relation.hasversionFerenbach DA, Ramdas V, Spencer N, Marson L, Anegon I, Hughes J and Kluth DC. Hemeoxygenase-1 expressing macrophages protect renal function after ischaemia/reperfusion injury. Molecular Therapy 2010; ePub Jun 15then
dc.relation.hasversionFerenbach D, Kluth D and Hughes J. Regulatory T cells and ischaemic injury: a brake on injury or an active promoter of tissue healing? Kidney International 2009; 76:689-91en
dc.relation.hasversionDevey L, Ferenbach D, Mohr E, Sangster K, Bellamy C, Hughes J, Soares M and Wigmore S. Tissue resident macrophages protect the liver from ischemia reperfusion injury via a Heme oxygenase-1 dependent mechanism. Molecular Therapy 2009; 17:65-72en
dc.relation.hasversionQi F, Adair A, Ferenbach D, Vass DG, Mylonas KJ, Kipari T, Clay M, Kluth DC, Hughes J and Marson LP. Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation. Transplantation 2008; 86:1267-74en
dc.relation.hasversionFerenbach D & Hughes J Macrophages and dendritic cells : what is the difference? Kidney International 2008; 74:5-7en
dc.relation.hasversionFerenbach D, Kluth DC, Hughes J. Inflammatory Cells in Renal Injury and Repair. Seminars in Nephrology. 2007;27:250-9en
dc.relation.hasversionKipari T, Cailhier J-F, Ferenbach D, Watson S, Houlberg K, Walbaum D, Clay S, Savill J & Hughes J. Nitric Oxide is an important mediator of renal tubular epithelial cell death in vitro and in murine experimental hydronephrosis. Am J Path. 2006;169:388-99en
dc.subjectmacrophageen
dc.subjectacute kidney injuryen
dc.subjectHeme oxygenase-1en
dc.subjectHO-1en
dc.titleRole of the macrophage in acute kidney injuryen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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