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Novel Therapies in Acute Kidney Injury

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Novel Therapies in Acute Kidney Injury NOVEL THERAPIES IN ACUTE KIDNEY INJURY A THESIS PRESENTED BY Dr SHOAB AHMED MEMON Registered at Bart’s and The London School of Medicine & Dentistry Queen Mary University of London, Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom For The degree of Doctor of Philosophy. 1 DECLARATION: I declare that this thesis is my own work and has not been submitted in any form for another degree or diploma at any university or other institution of tertiary education. Information derived from the work of others has been acknowledged in the text and a list of references is given. 1st July 2014 ____________________________ __________________ (Signature) (Date) 2 Contents List of figures: ............................................................................................................... 7 List of Tables ................................................................................................................. 8 Units and symbols ...................................................................................................... 13 Routes of administration and statistical terms......................................................... 14 Abstract ........................................................................................................................ 15 Acknowledgements ..................................................................................................... 17 CHAPTER 1 .................................................................................................................. 18 INTRODUCTION ........................................................................................................... 18 1.1: Acute kidney injury (AKI)..................................................................................... 19 1.2: Renal ischaemia reperfusion injury: .................................................................. 26 1.2.1 Pathophysiology and basic mechanism ................................................... 26 1.2.2: Inflammation during renal IRI ................................................................... 30 1.2.3: Oxidative stress during renal IRI .............................................................. 34 1.2.4: Apoptosis and necrosis ............................................................................ 37 1.3: Nitrite and its role in ischaemic conditions: ...................................................... 42 1.4: Thiamine and benfotiamine:................................................................................ 45 1.5: Bone morphogenic protein-7: ............................................................................. 50 1.6: Aim and hypothesis: ............................................................................................ 53 1.6.1 Nitrite study ................................................................................................. 53 1.6.2 Thiamine study ............................................................................................ 53 1.6.3 BMP-7 in renal IRI study ............................................................................. 53 CHAPTER 2 .................................................................................................................. 54 EFFECTS OF LOW AND HIGH DIETARY NITRITE ON AKI ....................................... 54 2.1: Introduction .......................................................................................................... 55 2.2. Materials and methods ........................................................................................ 57 2.2.1. Rat model of renal IRI ................................................................................ 57 2.2.2 Assessment of renal function .................................................................... 58 2.2.3 Experimental design ................................................................................... 58 - - 2.2.4 Plasma NO2 /NO3 measurement by Griess assay .................................... 58 2.2.5 HK-2 Cells .................................................................................................... 59 2.2.6 In vitro ischaemia reperfusion injury model ............................................. 60 2.2.7 Cell viability assay ...................................................................................... 61 2.2.8 Serum starvation model ............................................................................. 61 3 2.2.9 Assessment of apoptosis ........................................................................... 62 2.2.9.1 Caspase activity ........................................................................................... 62 2.2.10 In vitro reperfusion model ........................................................................ 63 2.2.11 LDH cytotoxicity assay ............................................................................. 63 2.2.12. Bicinchoninic (BCA) assay ...................................................................... 64 2.2.13 Materials..................................................................................................... 65 2.2.14: Statistical analysis ................................................................................... 65 2.3 Results ................................................................................................................... 66 2.3.1: Sodium nitrite (NaNO2) protects HK-2 cells against apoptosis caused by serum starvation (SS) .......................................................................................... 66 2.3.2 NaNO2 protects HK-2 cells against in vitro IRI induced apoptosis ......... 68 2.3.3 Effects of NaNO2 on HK-2 cell necrosis .................................................... 69 2.2.4: Pre-treatment with NaNO2 does not prevent apoptosis at several doses ............................................................................................................................... 70 2.2.5: Pre-treatment with NaNO2 does not preserve cell viability at several doses ..................................................................................................................... 71 - - 2.3.6: Plasma NO2 /NO3 levels ............................................................................. 72 2.3.7: Effect of NaNO2 on renal IRI in rats .......................................................... 73 2.4 Discussion ............................................................................................................. 75 CHAPTER 3 .................................................................................................................. 79 ROLE OF THIAMINE AND BENFOTIAMINE IN AKI ................................................... 79 3.1: Introduction .......................................................................................................... 80 3.2 Materials and methods ......................................................................................... 84 3.2.1 Rat model of renal IRI ................................................................................. 84 3.2.2 Assessment of renal function .................................................................... 84 3.2.3 Experimental design ................................................................................... 84 3.2.4: Histological evaluation .............................................................................. 85 3.2.5 Terminal deoxynucleotide transferase nick end labeling (TUNEL) assay ............................................................................................................................... 85 3.2.6 Tissue extracts ............................................................................................ 86 3.2.7 ROS detection ............................................................................................. 87 3.2.8 End products of lipid peroxidation ............................................................ 88 3.2.9 Myeloperoxidase activity ............................................................................ 88 3.2.10. Western blot analysis .............................................................................. 89 3.2.11 Administration of benfotiamine ............................................................... 89 3.2.12 Experimental design ................................................................................. 90 4 3.2.13 In vitro IRI model ....................................................................................... 90 3.2.14 LDH cytotoxicity assay ............................................................................. 90 3.2.15 Cell viability (MTS) assay ......................................................................... 90 3.2.16 Serum starvation model ........................................................................... 90 3.2.17 Materials and statistical analysis ............................................................. 90 3.3 Results ................................................................................................................... 91 3.3.1: Thiamine attenuates apoptosis in HK-2 cultures in renal IRI (in vitro model) ................................................................................................................... 91 3.3.2: Effects of thiamine on necrosis caused by in vitro reperfusion model 92 3.3.3 Thiamine ameliorates renal dysfunction and attenuates the histological
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