Adrenal Remodeling and Dysfunction Parallel Age‐Dependent Hypertension in Spontaneously Hypertensive Rats

BACKGROUND: The adrenal gland plays a pivotal role in blood pressure regulation through the secretion of corticosteroids and catecholamines. While its contribution to secondary hypertension is well recognized, its role in essential hypertension remains incompletely understood. This study aimed to investigate whether structural and functional adrenal alterations precede or accompany the development of hypertension and to define the temporal relationship between adrenal remodeling and blood pressure elevation. METHODS: We systematically examined adrenal morphology, hormone secretion, enzyme expression, ultrastructure, and mitochondrial function in spontaneously hypertensive rats and normotensive Wistar-Kyoto controls across key developmental stages from ages 4 to 24 weeks. RESULTS: Spontaneously hypertensive rats developed progressive hypertension beginning at age 8 weeks, accompanied by disrupted circadian blood pressure rhythms. Notably, levels of aldosterone, corticosterone, and catecholamines were elevated in spontaneously hypertensive rats as early as 4 weeks, before overt hypertension. These hormonal changes were associated with zona glomerulosa thickening, increased Ki-67-positive proliferative activity, and upregulation of steroidogenic and catecholaminergic enzymes (aldosterone synthase, 11β-hydroxylase, and tyrosine hydroxylase). Ultrastructural remodeling included dense-core granule accumulation, smooth endoplasmic reticulum expansion, mitochondrial swelling, and cristae disruption. Functionally, adrenal ATP production and mitochondrial membrane potential were reduced, while oxidative stress intensified, as shown by decreased superoxide dismutase and glutathione and increased malondialdehyde levels. CONCLUSIONS: These findings suggest that adrenal hyperfunction and structural remodeling preceded and contributed to the onset and progression of hypertension in spontaneously hypertensive rats. This study highlights the adrenal gland as a dynamic and early modulator in essential hypertension and a promising target for therapeutic intervention.