Retinoic Acid Receptor-dependent Endogenous Retinoic Acid Activity in Mouse Collecting Ducts

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Abstract

    Retinoic acid (RA) is the main endogenous bioactive form of vitamin A that plays im¬portant role in many biological events by regulating gene expression. One of the major mechanisms via which endogenous RA regulate gene expression is through the canoni¬cal signalling, which involves binding and activation of RA receptors (RARs) by RA. It is well-acknowledged that the canonical signalling of endogenous RA is indispensable for embryonic kidney development but its role in the kidney after birth is not as well-established. It is hypothesised that the canonical signalling of endogenous RA continues to regulate gene expression in the kidney after birth. In the kidney of young and adult RARE-hsp68-lacZ mice, a constitutive signal of RA response element (RARE) activa¬tion was observed. The signal was largely localised to collecting duct principal cells, inner medullary collecting duct cells, and intercalated cells. In concordance with the in vivo observation, basal RARE activity was detected in mIMCD-3 cells, a cell line derived from mouse inner medullary collecting ducts. The RARE activity was likely a result of constitutive activation of RARs given rise by cell-autonomous synthesis of en¬dogenous RA as the activity was suppressed by antagonists of RARs and by an inhibitor of RA synthesising enzymes. Using mIMCD-3 cells as an in vitro model, target genes of endogenous RA/RARs were identified using microarray at the whole genome level, and the results were validated with reverse transcription quantitative polymerase chain reaction. Gene ontology analysis on the validated genes suggests their involvement in vitamin A metabolism, as well as in some classical and novel functions of collecting ducts including kidney development.
    Date of Award2012
    Original languageEnglish
    Awarding Institution
    • King's College London
    SupervisorQihe Xu (Supervisor) & Bruce Hendry (Supervisor)

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