The human adrenal cortex can be divided into distinct zones that have both morphologic and biochemical differences. The production of aldosterone in the zona glomerulosa and cortisol in the zona fasciculate can be traced to the zone-specific expression of the enzymes involved in steroid biosynthesis. This is particularly true for aldosterone synthase (CYP11B2) and 112-hydroxylase (CYP11B1). Our preliminary data suggest that three nuclear hormone receptors play pivotal roles in determining a glomerulosa versus fasciculata phenotype. Herein, we test the overall hypothesis that zone-specific expression of CYP11B2 and CYP11B1 results from the opposing activities of nuclear hormone receptors that differ between the glomerulosa and fasciculata. This hypothesis will be tested by the studies proposed in four Specific Aims: The experiments proposed in Specific Aim One will extend the applicant's ongoing project that has defined the regulatory elements in the 5'-flanking region of CYP11B2 gene. The proposed studies will complete the definition of the trans-acting factors responsible for glomerulosa specific expression of CYP11B2. Focus will be placed on the role of nuclear receptor, NURR1 (NR4A2), which stimulates CYP11B2 promoter activity, is up-regulated by angiotensin II and is expressed primarily in the zona glomerulosa.
Specific Aim Two will determine the mechanisms responsible for the lack of CYP11B2 seen in the glomerulosa. Preliminary studies indicate that the nuclear receptor, steroidogenic factor 1 (SF-1;NR5A1) is a potent repressor of CYP11B2 but potent activator of CYP11B1. These data support a role for SF-1 activity in the transition of glomerulosa to fasciculata.
Specific Aim 3 will determine the role of nuclear hormone receptor post-translational modification in the development of a glomerulosa cell phenotype. Preliminary data indicate that the glomerulosa has elevated sumoylation activities and sumoylation of SF-1 regulates its activity.
Specific Aim 4 will define the cis-regulatory elements and trans-acting factors responsible for silencing CYP11B2 expression in the fasciculata. We have isolated a 100 bp insert that is present in the CYP11B2 but not CYP11B1 gene. Preliminary data support the possibility that this insert includes a silencer sequence that acts to block fasciculata cell expression of CYP11B2. SIGNIFICANCE: Primary aldosteronsism (PA) is estimated to occur in 8 % of the hypertensive population. Most PA cases are caused by nodular hyperplasia or aldosterone-producing adenoma. A disruption in the normal regulation of CYP11B2 expression appears to be an important part of this disease process. The proposed studies will provide a detailed understanding of the molecular mechanisms regulating CYP11B2 expression within the normal adrenal and should provide insight into diseases of aldosterone excess including hyperaldosteronism.

Public Health Relevance

Narrative Information obtained from these studies will determine the molecular mechanisms causing zone- specific expression of CYP11B2 and CYP11B1 thereby advancing our understanding of adrenal zonation. In addition, the proposed studies will help to better define the causes of diseases of adrenal steroid excess including hyperaldosteronism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043140-19
Application #
8308006
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Margolis, Ronald N
Project Start
1997-09-01
Project End
2012-10-31
Budget Start
2012-08-01
Budget End
2012-10-31
Support Year
19
Fiscal Year
2012
Total Cost
$130,131
Indirect Cost
$41,607
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Nanba, Kazutaka; Chen, Andrew X; Omata, Kei et al. (2016) Molecular Heterogeneity in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab 101:999-1007
Monticone, Silvia; Else, Tobias; Mulatero, Paolo et al. (2015) Understanding primary aldosteronism: impact of next generation sequencing and expression profiling. Mol Cell Endocrinol 399:311-20
Nishimoto, Koshiro; Tomlins, Scott A; Kuick, Rork et al. (2015) Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A 112:E4591-9
Chen, Andrew X; Nishimoto, Koshiro; Nanba, Kazutaka et al. (2015) Potassium channels related to primary aldosteronism: Expression similarities and differences between human and rat adrenals. Mol Cell Endocrinol 417:141-8
Rege, Juilee; Nishimoto, Hiromi Koso; Nishimoto, Koshiro et al. (2015) Bone Morphogenetic Protein-4 (BMP4): A Paracrine Regulator of Human Adrenal C19 Steroid Synthesis. Endocrinology 156:2530-40
Nanba, Kazutaka; Chen, Andrew; Nishimoto, Koshiro et al. (2015) Role of Ca(2+)/calmodulin-dependent protein kinase kinase in adrenal aldosterone production. Endocrinology 156:1750-6
Nishimoto, Koshiro; Harris, Ruth B S; Rainey, William E et al. (2014) Sodium deficiency regulates rat adrenal zona glomerulosa gene expression. Endocrinology 155:1363-72
Gomez-Sanchez, Celso E; Qi, Xin; Velarde-Miranda, Carolina et al. (2014) Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol 383:111-7
Nishimoto, Koshiro; Rainey, William E; Bollag, Wendy B et al. (2013) Lessons from the gene expression pattern of the rat zona glomerulosa. Mol Cell Endocrinol 371:107-13
Monticone, Silvia; Hattangady, Namita G; Penton, David et al. (2013) a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J Clin Endocrinol Metab 98:E1861-5

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