Phone: (706) 721-7665
Fax: (706) 721-8360

Email: wrainey@mcg.edu
Office: CA-3094

The human adrenal cortex acts as a compound endocrine gland that secretes mineralocorticoids, glucocorticoids and the so-called adrenal androgens. These steroids arise from distinct zone of the adrenal cortex that have both morphologic and biochemical differences. Neither the origin of the stem cells of the cortical zones nor the mechanisms leading to the zone-specific production of steroids is clearly defined. The functional zonation of the adrenal cortex can be traced to the zone-specific expression of the enzymes involved in steroid biosynthesis. Here we take the novel approach of focusing on the molecular mechanisms that regulate the development of a glomerulosa, fasiculata or reticularis phenotype. We propose to define the mechanisms that regulate adrenal cell expression of key enzymes that directly impact the ability of adrenal cells to produce aldosterone, cortisol or DHEA-S. The proposed studies will provide insight into the normal physiology of the adrenal as well as pathologies associated with dysregulation of adrenal steroids.

There is growing evidence that chronic inappropriate elevations in circulating aldosterone occur leading to renal, cardiovascular and other pathologic complications. Primary aldosteronism is a major cause of endocrine hypertension and has been proposed to affect ~10% of the hypertensive population. The most common causes of primary aldosteronism are aldosterone-producing adenoma (APA) and nodular hyperplasia, which occur in part due to the disruption of the tightly regulated and site-specific expression of CYP11B2 (aldosterone synthase). The suppressed renin levels seen in patients with primary aldosteronism suggest that APA are not ANG II driven. APAs have in common elevated expression of aldosterone synthase, the enzyme responsible for the final step in aldosterone biosynthesis and usually expressed only in the adrenal zona glomerulosa. While the renin/angiotensin II/aldosterone axis is normally tightly controlled via negative feedback, in APA cells have lost normal regulatory processes and continue to produce aldosterone under low-renin conditions. A comparison of expression between APA and normal adrenal tissue indicated elevated levels of g-protein coupled receptors that are normally not seen in adrenocortical tissue. We are currently working to test the hypothesis that ectopic expression of GPCR in these adenomas mediates the pathophysiology of APA. These studies may identify novel targets for medical management of APA.

Post Docs
Ping Ye- MD PhD
Yasuhiro Nakamura- MD PhD
Modupe Awonuga- MD
Christine Rigsby- PhD

Students
Edson Nogueira - MD
Jeniel Parmar
Yewei Xing

Technicians
Claudia Vargas
Rebecca Key
Richard Lupo
Bobbie Mayhew (in Dallas)

Go to PubMed

Saner-Amigh K, Mayhew BA, Mantero F, Schiavi F, White PC, Rao CV, Rainey WE.2006 Elevated expression of luteinizing hormone receptor in aldosterone-producing adenomas J Clin Endocrinol Metab. 91:1136-42

Sirianni R, Mayhew BA, Carr BR, Parker CR Jr. Rainey WE. Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells. J Clin Endocrinol Metab 90:5393-5400.

Bassett MH, Mayhew B, Rehman K, White PC, Mantero F, Arnaldi G, Stewart PM, Bujalska I, Rainey WE. 2005 Expression profiles for steroidogenic enzymes in adrenocortical disease. J Clin Endocrinol Metab 90:5446-5455.

Seely J, Amigh, KS, Suzuki T, Mayhew B, Sasano H, Giguere V, Laganiere J, Carr BR, Rainey WE. 2005 Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha. Endocrinology. 146:3605-1613.

Havelock JC, Smith AL, Seely JB, Dooley CA, Rodgers RJ, Rainey WE, Carr BR. 2005 The NGFI-B family of transcription factors regulates expression of 3beta hydroxysteroid dehydrogenase type 2 in the human ovary. Mol Hum Reprod.11:79-85

Kurihara I, Shibata H, Kobayashi S, Suda N, Ikeda Y, Yokota K, Murai A, Saito I, Rainey WE, Saruta T. 2005 Ubc9 and PIAS1 activate COUP-TFI mediated human CYP11B2 gene transcription. J Biol Chem. 280:6721-30.

Havelock JC, Smith AL, Seely JB, Dooley CA, Rodgers RJ, Rainey WE, Carr BR. The NGFI-B family of transcription factors regulates expression of 3beta hydroxysteroid dehydrogenase type 2 in the human ovary. Mol Hum Reprod. ;11:79-85,2005

Sirianni R, Rehman KS, Carr BR, Parker Jr CR, Rainey WE Corticotropin-releasing hormone (CRH) directly stimulates cortisol and the cortisol biosynthetic pathway in human fetal adrenal cells J Clin Endocrinol Metab. 90:279-85., 2005

Saner KJ, Suzuki T, Sasano H, Pizzey J, Ho C, Strauss JF 3rd, Carr BR, Rainey WE Steroid sulfotransferase (SULT2A1) gene transcription is regulated by steroidogenic factor 1 (SF1) and GATA-6 in the human adrenal Mol Endocrinol 19:184-197, 2004

Bassett MH, Suzuki T, Sasano H, De Vries CJ, Jimenez PT, Carr BR, Rainey WE The orphan nuclear receptor NGFIB regulates transcription of 3beta-hydroxysteroid dehydrogenase. implications for the control of adrenal functional zonation J Biol Chem 279:37622-30,2004