Search Results
You are looking at 1 - 4 of 4 items for
- Author: Peter J Morgan x
- Refine by access: All content x
Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia
Tufts Medical Center, Boston, Massachusetts, USA
Search for other papers by Elizabeth K Fletcher in
Google Scholar
PubMed
Search for other papers by Monica Kanki in
Google Scholar
PubMed
Search for other papers by James Morgan in
Google Scholar
PubMed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
Search for other papers by David W Ray in
Google Scholar
PubMed
Search for other papers by Lea M Delbridge in
Google Scholar
PubMed
Search for other papers by Peter J Fuller in
Google Scholar
PubMed
Search for other papers by Colin D Clyne in
Google Scholar
PubMed
Search for other papers by Morag J Young in
Google Scholar
PubMed
We previously identified a critical pathogenic role for mineralocorticoid receptor (MR) activation in cardiomyocytes that included a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, studies on MR interactions with circadian clock signalling are limited. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa. Aldosterone or corticosterone (10 nM) regulated Cry1, Per1, Per2 and ReverbA (Nr1d1) gene expression patterns in H9c2 cells over 24 h. MR-dependent regulation of circadian gene promoters containing GREs and E-box sequences was established for CLOCK, Bmal, CRY1 and CRY2, PER1 and PER2 and transcriptional activators CLOCK and Bmal modulated MR-dependent transcription of a subset of these promoters. We also demonstrated differential regulation of MR target gene expression in hearts of mice 4 h after administration of aldosterone at 08:00 h vs 20:00 h. Our data support MR regulation of a subset of circadian genes, with endogenous circadian transcription factors CLOCK and BMAL modulating the response. This unsuspected relationship links MR in the heart to circadian rhythmicity at the molecular level and has important implications for the biology of MR signalling in response to aldosterone as well as cortisol. These data are consistent with MR signalling in the brain where, like the heart, it preferentially responds to cortisol. Given the undisputed requirement for diurnal cortisol release in the entrainment of peripheral clocks, the present study highlights the MR as an important mechanism for transducing the circadian actions of cortisol in addition to glucocorticoid receptor (GR) in the heart.
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
Department of General Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Search for other papers by Gregory S Y Ong in
Google Scholar
PubMed
Search for other papers by Timothy J Cole in
Google Scholar
PubMed
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia
Search for other papers by Gregory H Tesch in
Google Scholar
PubMed
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
Search for other papers by James Morgan in
Google Scholar
PubMed
Royal College of Surgeons in Ireland, Dublin, Ireland
Search for other papers by Jennifer K Dowling in
Google Scholar
PubMed
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
Search for other papers by Ashley Mansell in
Google Scholar
PubMed
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
Search for other papers by Peter J Fuller in
Google Scholar
PubMed
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
Search for other papers by Morag J Young in
Google Scholar
PubMed
MR activation in macrophages is critical for the development of cardiac inflammation and fibrosis. We previously showed that MR activation modifies macrophage pro-inflammatory signalling, changing the cardiac tissue response to injury via both direct gene transcription and JNK/AP-1 second messenger pathways. In contrast, MR-mediated renal electrolyte homeostasis is critically determined by DNA-binding-dependent processes. Hence, ascertaining the relative contribution of MR actions via DNA binding or alternative pathways on macrophage behaviour and cardiac inflammation may provide therapeutic opportunities which separate the cardioprotective effects of MR antagonists from their undesirable renal potassium-conserving effects. We developed new macrophage cell lines either lacking MR or harbouring a mutant MR incapable of DNA binding. Western blot analysis demonstrated that MR DNA binding is required for lipopolysaccharide (LPS), but not phorbol 12-myristate-13-acetate (PMA), induction of the MAPK/pJNK pathway in macrophages. Quantitative RTPCR for pro-inflammatory and pro-fibrotic targets revealed subsets of LPS- and PMA-induced genes that were either enhanced or repressed by the MR via actions that do not always require direct MR-DNA binding. Analysis of the MR target gene and profibrotic factor MMP12 identified promoter elements that are regulated by combined MR/MAPK/JNK signalling. Evaluation of cardiac tissue responses to an 8-day DOC/salt challenge in mice selectively lacking MR DNA-binding in macrophages demonstrated levels of inflammatory markers equivalent to WT, indicating non-DNA binding-dependent MR signalling in macrophages is sufficient for DOC/salt-induced tissue inflammation. Our data demonstrate that the MR regulates a macrophage pro-inflammatory phenotype and cardiac tissue inflammation, partially via pathways that do not require DNA binding.
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Perry Barrett in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Elena Ivanova in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by E Scott Graham in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Alexander W Ross in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Dana Wilson in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Helene Plé in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Julian G Mercer in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Francis J Ebling in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Sandrine Schuhler in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Sandrine M Dupré in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Andrew Loudon in
Google Scholar
PubMed
Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK
School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
Search for other papers by Peter J Morgan in
Google Scholar
PubMed
Tanycytes in the ependymal layer of the third ventricle act both as a barrier and a communication gateway between the cerebrospinal fluid, brain and portal blood supply to the pituitary gland. However, the range, importance and mechanisms involved in the function of tanycytes remain to be explored. In this study, we have utilized a photoperiodic animal to examine the expression of three unrelated gene sequences in relation to photoperiod-induced changes in seasonal physiology and behaviour. We demonstrate that cellular retinoic acid-binding protein 1 (CRBP1), a retinoic acid transport protein, GPR50, an orphan G-protein-coupled receptor and nestin, an intermediate filament protein, are down-regulated in short-day photoperiods. The distribution of the three sequences is very similar, with expression located in cells with tanycyte morphology in the region of the ependymal layer where tanycytes are located. Furthermore, CRBP1 expression in the ependymal layer is shown to be independent of a circadian clock and altered testosterone levels associated with testicular regression in short photo-period. Pinealectomy of Siberian hamsters demonstrates CRBP1 expression is likely to be dependent on melatonin output from the pineal gland. This provides evidence that tanycytes are seasonally responsive cells and are likely to be an important part of the mechanism to facilitate seasonal physiology and behaviour in the Siberian hamster.
Search for other papers by Perry Barrett in
Google Scholar
PubMed
Search for other papers by Elena Ivanova in
Google Scholar
PubMed
Search for other papers by E Scott Graham in
Google Scholar
PubMed
Search for other papers by Alexander W Ross in
Google Scholar
PubMed
Search for other papers by Dana Wilson in
Google Scholar
PubMed
Search for other papers by Helene Plé in
Google Scholar
PubMed
Search for other papers by Julian G Mercer in
Google Scholar
PubMed
Search for other papers by Francis J Ebling in
Google Scholar
PubMed
Search for other papers by Sandrine Schuhler in
Google Scholar
PubMed
Search for other papers by Sandrine M Dupré in
Google Scholar
PubMed
Search for other papers by Andrew Loudon in
Google Scholar
PubMed
Search for other papers by Peter J Morgan in
Google Scholar
PubMed
