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Lauren Smiley 000295934 Group 6: Cushing’s Disease Title: Sodium and Retinoic Acid in Relation to Cushing’s Syndrome Name

: Lauren Smiley Introduction: Individuals diagnosed with Cushing’s Syndrome have excess levels of adrenocorticotropic hormone. The two articles shown below discuss the relationships of sodium, retinoic acid, and the high levels of ACTH in individuals with Cushing’s Syndrome. Objective: The objective of the first study was to access the effect of excess adrenocorticotropic hormone on renal sodium homeostasis. The objective of the second study was to study the potential action of BMP-4 in corticotrophinoma growth. Materials and Methods: In the first study, mice were used to study the effect of chronic ACTH secretion on renal sodium handling. The mice were infused with ACTH or saline through an osmotic minipump for 2 weeks before being anesthetized for renal function experiments. The second study used AtT-20 pituitary corticotroph tumor cells from the American Type Culture Collections. The cells were cultured in a 5% CO2 atmosphere at 37 C in DMEM (ph 7.3) supplemented with 10% fetal calf serum (FCS), 2.2 g/liter NaHCO3, 10 mm HEPES, and 2 mM glutamine until the solution was amalgamated. Then the cells were treated with a mixture of either 10, 50, 100, or 200 ng/ml BMP-4, 0.001-1 uM noggin (which is a BMP-4and TGF-beta inhibitor), 10 ng/ml TGF-B, or 10 or 100 nM all-trans retinoic acid, dissolved in ethanol-DMSO as 10 mM stock solution. Results: The results of the first study showed that ACTH treated mice had increased corticosterone and aldosterone plasma levels, in addition to high hematocrit levels and a depletion of plasma volume. The mean arterial blood pressure was elevated in mice exposed to ACTH. Indicating that high levels of ACTH can result in a reduction in fractional sodium excretion, which can lead to hypertension. The results of the second study showed that BMP-4 inhibits corticotroph tumor cell ACTH secrection and cell proliferation. And also that an overall reduced BMP-4 expression was observed in Cushing’s disease adenomas when compared with normal corticotroph cells. Summary and Discussion: In the first study, ACTH infusion induces a pressor response in humans and animals, associated with reduced sodium excretion. However, in this study, strict dietary sodium restriction prevented this response to ACTH excess. This suggested that the ENaC-mediated sodium reabsorption is an important hypertensive event. This study also showed that restricting sodium intake and using certain drugs that increase epithelial sodium channel activity, ACTH induced hypertension can be prevented or controlled. The second study demonstrates that BMP-4 expression is reduced in corticotrophinoma cells and that BMP-4 regulates corticotroph cell physiology and also inhibits its tumorigenic potential. This inhibitory effect of BMP-4 constitutes the major mechanism for pituitary corticotroph pathogenesis. They also found that retinoic acid, which inhibits corticotrophinoma cells growth, may act through BMP-4 expression in corticotroph cells. Therefore, BMP-4 induction by retinoic acid may be used as a therapeutic treatment in individuals with Cushing’s disease. References: 1. Bailey MA, Mullins JJ, Kenyon CJ. Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome. Hypertension. 2009;54:890-896. 2. Giacomini D, Páez-Pereda M, Theodoropoulou M, Labeur M, Refojo D, Gerez J, Chervin A, Berner S, Losa M, Buchfelder M, Renner U, Stalla GK, Arzt E. Bone Morphogenetic Protein-4 Inhibits Corticotroph Tumor Cells: Involvement in the Retinoic Acid Inhibitory Action. Endocrinology. 2006;147:247-256.