Primary Aldosteronism Takes (KCNJ)Five!

Abstract

Primary aldosteronism (PA) is the most common form of endocrine hypertension, due to autonomous aldosterone production from the adrenal cortex. Patients with PA typically present with hypertension, high plasma aldosterone levels associated with low plasma renin activity, and varying degrees of hypokalemia and metabolic alkalosis (1). The prevalence of PA increases with the severity of hypertension and is currently estimated around 10% in referred patients and 4% in primary care (2, 3) but as high as 20% in patients with resistant hypertension (4, 5). The two main causes of PA are aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), also called idiopathic hyperaldosteronism. Efficient and timely screening for PA is of major importance, given the severe cardiovascular outcome of aldosterone excess that is independent of blood pressure levels (6, 7). Yet, the pathogenic mechanisms leading to aldosterone hypersecretion and cell proliferation are largely unknown. Recently, a few recurrent somatic mutations of the potassium inwardly-rectifying channel, subfamily J, member 5 (KCNJ5) gene, coding for the potassium channel Kir3.4, have been implicated as a cause of APA, whereas an inherited mutation was identified in a family with a Mendelian form of early severe hypertension that features massive adrenal hyperplasia and is referred to as familial hyperaldosteronism type 3 (FH3) (8, 9). These mutations all lie near or within the selectivity filter of the Kir3.4 channel; they result in a loss of channel selectivity, with increased sodium conductance leading to membrane depolarization. These changes are presumed to be responsible for constitutive aldosterone secretion and cell proliferation by promoting opening of membrane voltage-dependent calcium channels that is followed by activation of the calcium signaling pathway, the main trigger for aldosterone production in adrenal zona glomerulosa cells. In this issue of Endocrinology, Oki et al. (10) now formally establish a causal relationship between KCNJ5 mutations and hyperaldosteronism. They demonstrate that the inherited KCNJ5 T158A mutation produces a marked stimulation in aldosterone biosynthesis that is dependent on membrane depolarization followed by calcium influx into adrenal cortical carcinoma cells (10). The paper by Oki et al. (10) indeed tackles a central issue that had not previously been addressed, i.e. the causal link between KCNJ5 mutations, membrane depolarization, aldosterone overproduction, and cell proliferation. By transiently infecting adrenocortical HAC15 cells with a lentivirus expressing wild-type KCNJ5 (potassium inwardly-rectifying channel, subfamily J, member 5) or mutated KCNJ5 T158A, the authors show that expression of channels harboring the T158A mutation potentiated basal aldosterone production, which was further stimulated by angiotensin II and the protein kinase A activator forskolin. Using different fluorescent dyes, they confirmed the enhanced sodium influx through the mutated Kir3.4 channel, leading to membrane depolarization and increased intracellular calcium concentrations. KCNJ5 T158A-transduced cells presented significantly increased expression of CYP11B2, the gene coding for aldosterone synthase, which ensures the last three enzymatic steps of aldosterone biosynthesis. Expression of CYP11B1, coding for 11 -hydroxylase, was also increased, as was basal and stimulated cortisol production. KCNJ5 T158A also induced significant production of 18-oxocortisol, a hybrid steroid largely produced in affected members of the original family with FH3 (11). CYP11B2 expression and al-