Targeted disruption of the Kcnj5 gene in the female mouse lowers aldosterone levels.
Clinical science (London, England : 1979)
Portland Press, Ltd.
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Hardege, I., Long, L., Al Maskari, R., Figg, N., & O'Shaughnessy, K. (2018). Targeted disruption of the Kcnj5 gene in the female mouse lowers aldosterone levels.. Clinical science (London, England : 1979), 132 (1), 145-156. https://doi.org/10.1042/cs20171285
Aldosterone is released from adrenal zona glomerulosa cells and plays an important role in Na and K homeostasis. Mutations in the human KCNJ5 gene encoding the GIRK4 potassium channel cause abnormal aldosterone secretion and hypertension. To better understand the role of wild-type (WT) GIRK4 in regulating aldosterone release we have looked at aldosterone secretion in a KCNJ5 knock-out (KO) mouse. We found that female, but not male, KO mice have reduced aldosterone levels compared to WT female controls, but higher levels of aldosterone after Ang-II stimulation. These differences could not be explained by sex-differences in CYP11B2 gene expression in the mouse adrenal. Using RNAseq analysis to compare WT and KO adrenals we showed that females also have a much larger set of differentially expressed adrenal genes than males (395 vs 7). Ingenuity Pathway Analysis of this gene set suggested that PPAR nuclear receptors regulate aldosterone production and altered signalling in the female KO mouse could explain the reduced aldosterone secretion. We tested this hypothesis in H295R adrenals cells and showed that the selective PPARα agonist fenofibrate can stimulate aldosterone production and induce CYP11B2. Dosing mice in vivo produced similar results. Together our data show that KCNJ5 is important for baseline aldosterone secretion, but its importance is sex-limited at least in the mouse. It also highlights a novel regulatory pathway for aldosterone secretion through PPARα that may have translational potential in human hyperaldosteronism.
Zona Glomerulosa, Cell Line, Tumor, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Aldosterone, Angiotensin II, Vasoconstrictor Agents, Gene Expression Profiling, Sex Factors, Female, Male, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Cytochrome P-450 CYP11B2
British Heart Foundation (FS/12/78/29875)
External DOI: https://doi.org/10.1042/cs20171285
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273274
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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