Adrenal decommissioning and hypertension

Summary

Principal Investigator: Elise P Gomez-Sanchez
Abstract: Aldosterone production by adrenal zona glomerulosa (ZG) cells is regulated by the renin-angiotensin system, potassium and, to a lesser extent, ACTH. Sodium depletion leads to an increase in the expression and activity of the enzyme aldosterone synthase. Persistent low salt intake increases the number of ZG cells, as well as aldosterone synthase; ZG cells are "commissioned." Upon return to a normal salt intake, aldosterone synthase expression decreases. Chronic high sodium intake further decreases aldosterone synthase expression and reduces the number of glomerulosa cells as well, in a process called "decommissioning" for this proposal. Excessive aldosterone is associated with hypertension, glomerular sclerosis, stroke, and cardiac hypertrophy and fibrosis in humans and experimental animals. Knowledge of the molecular mechanisms involved in ZG decommissioning would guide more effective measures to prevent and treat these diseases. Aim 1: ZG decomissioning in Wistar rats that have been subjected to chronic sodium depletion, then acutely repleted with sodium will be studied. The role of apoptosis in the decrease in width of the ZG in decommissioning will be assessed using immunohistochemical (ihc). Real time RT-PCR, Western blots and ihc will be used to demonstrate the role, if any, of genes expressed in the ZG, but not in the rest of the adrenal, that we have recently identified. Changes in gene expression at during decommissioning will be demonstrated using a Laser Capture Microdissection and cDNA microarray technique used successfully by us before, clones will be verified, then mRNA and protein levels for candidate genes, those with the greatest changes and or recognized as being involved in major cell regulatory processes will be studied. Aim 2: Study the ZG in the SHR-SP during chronic sodium loading when the expression of aldosterone synthase in this strain of rat increases, rather than decreases as in normal individuals. Using similar protocols as those in Aim 1, we will study and compare the process of adrenal decommissioning between SHR-SP and regular SHR rats with emphasis of the ZG genes identified as important in Aim 1.
Funding Period: 2003-12-15 - 2008-11-30
more information: NIH RePORT

Top Publications

  1. pmc A mutation in the start codon of γ-crystallin D leads to nuclear cataracts in the Dahl SS/Jr-Ctr strain
    Ashley C Johnson
    Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS 39216, USA
    Mamm Genome 24:95-104. 2013
  2. pmc Angiotensin II-regulated transcription regulatory genes in adrenal steroidogenesis
    Damian G Romero
    Endocrinology, G V Sonny Montgomery Department of Veterans Affairs Medical Center, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
    Physiol Genomics 42:259-66. 2010
  3. pmc Central regulation of blood pressure by the mineralocorticoid receptor
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center, 1500 Woodrow Wilson Dr, Jackson, MS 39216, USA
    Mol Cell Endocrinol 350:289-98. 2012
  4. pmc Mineralocorticoid receptors in the brain and cardiovascular regulation: minority rule?
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center and Department of Medicine, Division of Endocrinology, The University of Mississippi Medical Center, Jackson, MO, USA
    Trends Endocrinol Metab 22:179-87. 2011
  5. pmc Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells
    Damian G Romero
    Division of Endocrinology, G V Sonny Montgomery Veterans Affairs Medical Center, and Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
    Endocrinology 149:2477-83. 2008
  6. pmc Immunohistochemical demonstration of the mineralocorticoid receptor, 11beta-hydroxysteroid dehydrogenase-1 and -2, and hexose-6-phosphate dehydrogenase in rat ovary
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery Veterans Affairs Medical Center and Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi, USA
    J Histochem Cytochem 57:633-41. 2009
  7. pmc Central mineralocorticoid receptors and cardiovascular disease
    Elise P Gomez Sanchez
    Division of Endocrinology, University of Mississippi Medical Center, Jackson VA Medical Center, Jackson, MS 39216, USA
    Neuroendocrinology 90:245-50. 2009
  8. pmc The mammalian mineralocorticoid receptor: tying down a promiscuous receptor
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, MS 39216, USA
    Exp Physiol 95:13-8. 2010
  9. pmc Aldosterone synthesis in the brain contributes to Dahl salt-sensitive rat hypertension
    Elise P Gomez-Sanchez
    Veterans Administration Medical Center 151, 1500 East Woodrow Wilson Drive, Jackson, MS, 39216 5199, USA
    Exp Physiol 95:120-30. 2010
  10. pmc Hexose-6-phosphate dehydrogenase and 11beta-hydroxysteroid dehydrogenase-1 tissue distribution in the rat
    Elise P Gomez-Sanchez
    Research Service, GV Sonny Montgomery Veterans Affairs Medical Center, Jackson, MS 39216, USA
    Endocrinology 149:525-33. 2008

Scientific Experts

Detail Information

Publications20

  1. pmc A mutation in the start codon of γ-crystallin D leads to nuclear cataracts in the Dahl SS/Jr-Ctr strain
    Ashley C Johnson
    Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS 39216, USA
    Mamm Genome 24:95-104. 2013
    ..In summary, the identification of the genetic cause in this novel cataract model may provide an opportunity to better understand the development of cataracts, particularly in the context of hypertension...
  2. pmc Angiotensin II-regulated transcription regulatory genes in adrenal steroidogenesis
    Damian G Romero
    Endocrinology, G V Sonny Montgomery Department of Veterans Affairs Medical Center, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
    Physiol Genomics 42:259-66. 2010
    ..These transcription regulatory genes may be involved in adrenal steroidogenesis pathologies; thus they merit additional study as potential candidates for therapeutic intervention...
  3. pmc Central regulation of blood pressure by the mineralocorticoid receptor
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center, 1500 Woodrow Wilson Dr, Jackson, MS 39216, USA
    Mol Cell Endocrinol 350:289-98. 2012
    ....
  4. pmc Mineralocorticoid receptors in the brain and cardiovascular regulation: minority rule?
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center and Department of Medicine, Division of Endocrinology, The University of Mississippi Medical Center, Jackson, MO, USA
    Trends Endocrinol Metab 22:179-87. 2011
    ..MR antagonists are valuable adjuncts to the treatment of chronic cardiovascular and renal disease; the crucial need to discover targets for development of selective therapy for specific MR functions is also discussed...
  5. pmc Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells
    Damian G Romero
    Division of Endocrinology, G V Sonny Montgomery Veterans Affairs Medical Center, and Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
    Endocrinology 149:2477-83. 2008
    ..Alterations in miRNA-21 expression levels or function may be involved in dysregulation of angiotensin II signaling and abnormal aldosterone secretion by adrenal glands in humans...
  6. pmc Immunohistochemical demonstration of the mineralocorticoid receptor, 11beta-hydroxysteroid dehydrogenase-1 and -2, and hexose-6-phosphate dehydrogenase in rat ovary
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery Veterans Affairs Medical Center and Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi, USA
    J Histochem Cytochem 57:633-41. 2009
    ..MR function in the ovary is as yet unclear, but distinct patterns of distribution of 11beta-HSD1 and -2 and H6PDH suggest that the ligand for MR activation in different cells of the ovary may be differentially regulated...
  7. pmc Central mineralocorticoid receptors and cardiovascular disease
    Elise P Gomez Sanchez
    Division of Endocrinology, University of Mississippi Medical Center, Jackson VA Medical Center, Jackson, MS 39216, USA
    Neuroendocrinology 90:245-50. 2009
    ..MR that pertain to the central modulation of cardiovascular function and health are addressed herein...
  8. pmc The mammalian mineralocorticoid receptor: tying down a promiscuous receptor
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, MS 39216, USA
    Exp Physiol 95:13-8. 2010
    ....
  9. pmc Aldosterone synthesis in the brain contributes to Dahl salt-sensitive rat hypertension
    Elise P Gomez-Sanchez
    Veterans Administration Medical Center 151, 1500 East Woodrow Wilson Drive, Jackson, MS, 39216 5199, USA
    Exp Physiol 95:120-30. 2010
    ..Aldosterone synthesis in brains of SS rats is greater than in SD rats and is important in the genesis of their salt-sensitive hypertension...
  10. pmc Hexose-6-phosphate dehydrogenase and 11beta-hydroxysteroid dehydrogenase-1 tissue distribution in the rat
    Elise P Gomez-Sanchez
    Research Service, GV Sonny Montgomery Veterans Affairs Medical Center, Jackson, MS 39216, USA
    Endocrinology 149:525-33. 2008
    ..This antibody against the H6PDH should prove useful for further studies of enzyme activity requiring NADPH generation within the endoplasmic reticulum...
  11. ncbi Gene expression profile in rat adrenal zona glomerulosa cells stimulated with aldosterone secretagogues
    Damian G Romero
    Division of Endocrinology, G V Sonny Montgomery Veterans Affairs Medical Center, Jackson, MS 39216, USA
    Physiol Genomics 32:117-27. 2007
    ..Increasing our knowledge of adrenal physiology and gene regulation in nontransformed cell systems could lead us to a better approach for the discovery of candidate genes involved in pathological conditions of the adrenal cortex...
  12. ncbi Is aldosterone synthesized within the rat brain?
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery VA Medical Center, 1500 E Woodrow Wilson Drive 151, Jackson, MS 39216, USA
    Am J Physiol Endocrinol Metab 288:E342-6. 2005
    ..It is postulated that the small amounts of aldosterone synthesized in the brain could provide a local ligand for autocrine or paracrine activation of the mineralocorticoid receptor...
  13. ncbi Interleukin-8 synthesis, regulation, and steroidogenic role in H295R human adrenocortical cells
    Damian G Romero
    Division of Endocrinology, The University of Mississippi Medical Center, Jackson, 39216, USA
    Endocrinology 147:891-8. 2006
    ....
  14. ncbi Development of a panel of monoclonal antibodies against the mineralocorticoid receptor
    Celso E Gomez-Sanchez
    Division of Endocrinology, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216, USA
    Endocrinology 147:1343-8. 2006
    ..In summary, several antibodies are described that recognize different parts of the MR that should facilitate the study of this important mediator of two classes of steroid hormone action...
  15. ncbi RGS2 is regulated by angiotensin II and functions as a negative feedback of aldosterone production in H295R human adrenocortical cells
    Damian G Romero
    Division of Endocrinology, Montgomery Veterans Administration Medical Center, USA
    Endocrinology 147:3889-97. 2006
    ..RGS2 alterations in expression levels or functionality could be implicated in deregulations of Ang II signaling and abnormal aldosterone secretion by the adrenal gland...
  16. ncbi Angiotensin II-mediated protein kinase D activation stimulates aldosterone and cortisol secretion in H295R human adrenocortical cells
    Damian G Romero
    Division of Endocrinology, Department of Medicine, Montgomery Veterans Affairs Medical Center, and The University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216, USA
    Endocrinology 147:6046-55. 2006
    ..These data provide new insights into the molecular mechanisms involved in angiotensin II-induced physiological and pathophysiological events in adrenal cells...
  17. ncbi Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion
    Damian G Romero
    Division of Endocrinology, Department of Medicine, Montgomery VA Medical Center and The University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
    Endocrinology 148:2644-52. 2007
    ..Dab2 may therefore be a modulator of aldosterone secretion and be involved in mineralocorticoid secretion abnormalities...
  18. ncbi Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis
    Damian G Romero
    Division of Endocrinology, G V Sonny Montgomery Veterans Affairs Medical Center, Jackson, Mississippi, USA
    Physiol Genomics 30:26-34. 2007
    ....
  19. ncbi Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion
    Damian G Romero
    Division of Endocrinology, G V Sonny Montgomery VA Medical Center, and Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
    J Endocrinol 194:429-40. 2007
    ..Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion...
  20. ncbi Effect of 3beta-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat
    Elise P Gomez-Sanchez
    Research Service, G V Sonny Montgomery Veterans Affairs Medical Center, Jackson, MS 39216, USA
    Am J Physiol Regul Integr Comp Physiol 288:R389-93. 2005
    ..These studies suggest that the synthesis in the brain of a mineralocorticoid receptor agonist, probably aldosterone, is responsible in part for the salt-induced hypertension of the inbred Dahl SS/jr rat...