Abstract P001: Comparative Study on Steroidgenic Activity in Aldosterone-Producing Adenoma With ATPase or CACNA1D Gene Mutations in Japanese Patients With Primary Aldosteronism
Object: Our aim is to clarify the regulatory mechanism of aldosterone synthesis in patients with aldosterone-producing adenomas (APA) harboring ATPase or CACNA1D gene mutations.
Design and patients: We subjected 108 patients with unilateral APA, and tested somatic mutations by using each APA tissue. ATPase and CACNA1D genes were analyzed among 33 APAs without KCNJ5 gene mutations. We also evaluated pathological findings of steroidgenic enzymes and isolated cells prepared from 2 ATP2B3- and 1 CACNA1D-mutated APAs were incubated with various stimulants for clarifying steroidgenic activity.
Results: There were 1, 2, and 2 cases whose APAs possessed ATP1A1, ATP2B3, and CACNA1D mutations, respectively. Compared with the wild-type group without any somatic mutations of KCNJ5, ATPase or CACNA1D, the patients with ATPase mutations showed severe phenotype of hyperaldosteronemia even with smaller-sized tumors, although the CACNA1D-mutated APA patients showed similar characteristics. Pathological findings clearly demonstrated that the ATPase-mutated APA was mainly composed of compact eosinophilic tumor cells, while the CACNA1D-mutated APA mainly did of clear tumor cells with relatively weak 3βHSD2 immunoreactivity. In vitro incubation study with isolated APA cells demonstrated that aldosterone production of ATP2B3 mutated APA cells was more responsive to (Bt)2cAMP than that of the other types of cells (almost 2-fold in the wild group and the CACNA1D-mutated cells vs. 4-fold increase in the ATPase-mutated cells). On the other hand, CACNA1D-mutated APA cells showed greater responsiveness to ACTH compared with the other types of cells (almost 2-fold in the wild group and ATPase-mutated cells vs. 4-fold increase in the CACNA1D-mutated cells).
Conclusion: Responsiveness of aldosterone production stimulated by ACTH or cyclic AMP differed in each case with different cell types. The mutation of ATPase seems to promote accelerated intracellular Ca signaling systems, of which activation may be quantitatively differed in the case of CACNA1D mutation. Thus, our data suggested that the regulatory effect of ACTH on aldosterone synthesis might vary according to the basal intracellular conditions, such as upregulation of Ca signaling induced by each mutation.
Author Disclosures: T. Kitamoto: None. S. Suematsu: None. Y. Matsuzawa: None. J. Saito: None. M. Omura: None. T. Nishikawa: None.
- © 2015 by American Heart Association, Inc.