Acid-Sensing Ion Channel 1a Deficiency Drives Endocrine Hypertension in Male Mice

Background Acid-sensing ion channel 1a (ASIC1a) is an H+-gated cation channel that responds to extracellular acidosis in both normal and pathological states, including ischemia, inflammation, and metabolic disturbances. While ASIC1a regulates vascular reactivity, its role in blood pressure regulation remains unclear, particularly concerning sex, aging, and disease. This study aims to investigate whether ASIC1a: 1) contributes to cardiovascular function in a sex-dependent manner; 2) plays a dynamic role in cardiovascular homeostasis with aging; and 3) modulates the development of angiotensin II-induced systemic hypertension.

Radiotelemeters were implanted in 6- and 18-month-old male and female wild-type (Asic1a+/+) and ASIC1a knockout (Asic1a-/-) mice to monitor mean arterial blood pressure and heart rate under baseline conditions and in response to angiotensin II. Blood gases, electrolytes, hormones, and end-organ injury were also assessed.

Aged male Asic1a-/- mice develop hypertension driven by aldosterone excess and sympathetic overactivity, which is accompanied by cardiac hypertrophy, aortic fibrosis, and glomerular hypertrophy. Female Asic1a-/- mice remain unaffected. In male Asic1a-/- mice, hyperaldosteronism occurs independent of the renin-angiotensin system and mitigates angiotensin II-induced hypertension. Furthermore, 6-month-old male Asic1a-/- mice exhibit elevated corticosterone, hypokalemia, reduced urine osmolality, increased pulse pressure, and cardiomyocyte hypertrophy that precedes hypertension.

These findings establish ASIC1a as a novel, sex-specific regulator of cardiovascular function, linking early corticosterone excess in male mice to hyperaldosteronism and implicating ASIC1a deficiency as a potential driver of endocrine-related hypertension. GRAPHICAL ABSTRACT Competing Interest Statement The authors have declared no competing interest. Footnotes This version of the manuscript has been revised to add supplemental text and figures. No other changes have been made. LIST OF ABBREVIATIONS (alphabetical) - ACTH - adrenocorticotropic hormone - Ang II - angiotensin II - ASIC1a (gene name ACCN2) - acid-sensing ion channel 1a - CBG - corticosteroid-binding globulin - CSA - cross-sectional area - Epi - epinephrine (adrenaline) - HR - heart rate - HPA - hypothalamus-pituitary-adrenal - 11β-HSD1/2 - 11β-hydroxysteroid dehydrogenase types 1 and 2 - MABP - mean arterial blood pressure - NE - norepinephrine (noradrenaline) - RAS - renin-angiotensin system - SGK1 - serum and glucocorticoid kinase 1 - SPL - spironolactone - SEM - standard error of the mean