Down-regulation of D2 dopamine receptor and increased protein kinase Cmu phosphorylation in aldosterone-producing adenoma play roles in aldosterone overproduction.
BACKGROUND
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 adenocarcinoma cells (H295R) was attenuated by the D2 agonist, bromocriptine (BMC). BMC selectively attenuated AII-induced protein kinase C (PKC)-mu phosphorylation and its translocation to the cell membrane. PKCmu-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 PKCmu levels in APA and the nontumorous adrenal cortex, expression of phosphorylated PKCmu in APA was much higher.


CONCLUSIONS
This is the first study to demonstrate that the D2R modulated aldosterone secretion and synthesis through a specific attenuation of PKCmu activity, as well as the intracellular calcium level. Down-regulation of the D2R in APA, in turn, increased PKCmu activity and led to overproduction of aldosterone in affected patients. The D2R may thus serve as a potential treatment target for primary aldosteronism.
Chang
Hong-Wei
HW
Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Sun South Road, Taipei, Taiwan 100.
Chu
Tzong-Shinn
TS
Huang
Hong-Yu
HY
Chueh
Shih-Chieh
SC
Wu
Vin-Cent
VC
Chen
Yung-Ming
YM
Hsieh
Bor-Shen
BS
Wu
Kwan-Dun
KD
D000306:Adrenal Cortex Neoplasms / Q000201:enzymology / Q000378:metabolism*; D018246:Adrenocortical Adenoma / Q000201:enzymology / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis* / Q000097:blood; D000804:Angiotensin II / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D011493:Protein Kinase C / Q000096:biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000502:physiology*; D050638:Receptors, Dopamine D4 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
D008565:Membrane Proteins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D000804:Angiotensin II; D050638:Receptors, Dopamine D4; D000450:Aldosterone; D015544:Inositol 1,4,5-Trisphosphate; D019405:Cytochrome P-450 CYP11B2; C089212:protein kinase D; D011493:Protein Kinase C; D002118:Calcium