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Down-Regulation of D2 Dopamine Receptor and Increased Protein Kinase Cµ Phosphorylation in Aldosterone-Producing Adenoma Play Roles in Aldosterone Overproduction

Nephrology Division (H.-W.C., T.-S.C., H.-Y.H., V.-C.W., Y.-M.C., B.-S.H., K.-D.W.), Department of Internal Medicine, and Department of Urology (S.-C.C.), National Taiwan University Hospital, Taipei, Taiwan 100

Address all correspondence and requests for reprints to: Kwan-Dun Wu, M.D., Ph.D., Room 1419, Clinical Research Building, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Sun South Road, Taipei, Taiwan 100. E-mail: kdw{at}ntumc.org.

Context: The mechanism associated with the overproduction of aldosterone by aldosterone-producing adenomas (APA) is unknown.

Objective: The objective of the study was to explore the role of the D2 dopamine receptor (D2R) on aldosterone synthesis and secretion and clarify the clinical importance of this role on aldosterone overproduction in APA.

Results: D2R expression in APA was examined in 24 patients and was much less than that in the nontumorous adrenal cortex. D2R mRNA levels in APA were inversely correlated with CYP11B2 mRNA levels and the patient’s plasma aldosterone concentration. Angiotensin II (AII)-stimulated aldosterone secretion and CYP11B2 mRNA expression in human adrenocarcinoma cells (H295R) was attenuated by the D2 agonist, bromocriptine (BMC). BMC selectively attenuated AII-induced protein kinase C (PKC)-µ phosphorylation and its translocation to the cell membrane. PKCµ-specific short-hairpin RNA significantly decreased AII-induced CYP11B2 mRNA expression and aldosterone secretion. BMC also attenuated the AII-induced increase in cytoplasmic calcium, partially through an inhibition of cytoplasmic inositol 1,4,5 triphosphate production. Despite similar total PKCµ levels in APA and the nontumorous adrenal cortex, expression of phosphorylated PKCµ in APA was much higher.

Conclusion: This is the first study to demonstrate that the D2R modulated aldosterone secretion and synthesis through a specific attenuation of PKCµ activity, as well as the intracellular calcium level. Down-regulation of the D2R in APA, in turn, increased PKCµ activity and led to overproduction of aldosterone in affected patients. The D2R may thus serve as a potential treatment target for primary aldosteronism.

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