Angiotensin II Receptor Signaling in the Hypothalamic-Pituitary-Adrenal Axis and Spleen After Spinal Cord Injury...

Spinal cord injury (SCI) disrupts the integrated neuroendocrine network linking the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system, and sympathetic nervous system, resulting in endocrine and immune dysfunction. However, the effects of SCI on angiotensin II receptor signaling remain unclear. This study investigated temporal and lesion-dependent changes in angiotensin II type 1 (AT₁) and type 2 (AT₂) receptor expression following SCI in rats. Low-thoracic SCI (Th9 compression, 40 g/15 min) was evaluated over 28 days, while acute responses to partial (Th9) versus near-complete (Th1) sympathoadrenal denervation were compared. Receptor expression was assessed in the hypothalamic paraventricular nucleus, pituitary, adrenal gland, and spleen, and correlated with hormonal and morphological alterations. Surgical stress alone activated systemic angiotensin II signaling. Low-thoracic SCI induced time- and tissue-specific changes in angiotensin receptor expression independent of circulating angiotensin II levels, indicating adaptive remodeling of HPA axis sensitivity. SCI caused transient adrenal enlargement, zona fasciculata hypertrophy, dysregulated HPA axis activity, angiotensin II-independent aldosterone production, and altered catecholamine secretion. Splenic AT₁ receptor expression showed early upregulation followed by compensatory downregulation, consistent with dynamic neuroimmune modulation. In contrast, high-thoracic SCI markedly reduced receptor expression across central and peripheral HPA axis components and the spleen, accompanied by decreased corticotropin-releasing hormone, aldosterone, and norepinephrine, stable adrenocorticotropic hormone, and elevated corticosterone and epinephrine. These findings demonstrate that the extent of sympathetic disruption critically determines neuroendocrine-immune responses after SCI and identify sympathetic innervation as a key regulator of angiotensin receptor balance and stress-axis homeostasis following spinal cord trauma.