Julia Schewe

Abstract Primary aldosteronism is characterized by at least partially autonomous production of the adrenal steroid hormone aldosterone and is the most common cause of secondary hypertension. The most frequent subforms are idiopathic hyperaldosteronism and aldosterone-producing adenoma. Rare causes include unilateral hyperplasia, adrenocortical carcinoma and Mendelian forms (familial hyperaldosteronism). Studies conducted in the last eight years have identified somatic driver mutations in a substantial portion of aldosterone-producing adenomas, including the genes KCNJ5 (encoding inwardly rectifying potassium channel GIRK4), CACNA1D (encoding a subunit of L-type voltage-gated calcium channel Ca V 1.3), ATP1A1 (encoding a subunit of Na + /K + -ATPase), ATP2B3 (encoding a Ca 2+ -ATPase), and CTNNB1 (encoding ß-catenin). In addition, aldosterone-producing cells were recently reported to form small clusters (aldosterone-producing cell clusters) beneath the adrenal capsule. Such clusters accumulate with age and appear to be more frequent in individuals with idiopathic hyperaldosteronism. The fact that they are associated with somatic mutations implicated in aldosterone-producing adenomas also suggests a precursor function for adenomas. Rare germline variants of CYP11B2 (encoding aldosterone synthase), CLCN2 (encoding voltage-gated chloride channel ClC-2), KCNJ5 , CACNA1H (encoding a subunit of T-type voltage-gated calcium channel Ca V 3.2), and CACNA1D have been reported in different subtypes of familial hyperaldosteronism. Collectively, these studies suggest that primary aldosteronism is largely due to genetic mutations in single genes, with potential implications for diagnosis and therapy.

Abstract Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). Here, we report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation. In these Clcn2 R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2 R180Q/+ mice have increased aldosterone:renin ratios as well as elevated blood pressure levels. The counterpart knockout model ( Clcn2 −/− ), in contrast, requires elevated renin levels to maintain normal aldosterone levels. Adrenal slices of Clcn2 R180Q/+ mice show increased calcium oscillatory activity. Together, our work provides a knockin mouse model with a mild form of primary aldosteronism, likely due to increased chloride efflux and depolarization. We demonstrate a role of ClC-2 in normal aldosterone production beyond the observed pathophysiology.

Significance Primary aldosteronism (increased production of the adrenal steroid hormone aldosterone) is the most common cause of secondary hypertension. We here generated a mouse model of familial hyperaldosteronism type IV with a heterozygous gain-of-function mutation in a calcium channel gene ( Cacna1h M1560V/+ ). Cacna1h M1560V/+ mice have about twofold elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism) and elevated blood pressure, with an overall mild phenotype. Elevated adrenal aldosterone synthase expression in Cacna1h M1560V/+ mice is associated with increased intracellular calcium concentrations in glomerulosa cells. This model allows for the ex vivo analysis of calcium signaling in aldosterone-producing glomerulosa cells of the adrenal gland. Cacna1h −/− mice have normal aldosterone synthase expression, with implications for the evaluation of CACNA1H as a therapeutic target.