Central Mechanisms of Angiotensin II Signaling Dysregulation in Neurogenic Hypertension

Abstract

Neurogenic hypertension is characterized by increased sympathetic activity and autonomic dysfunction. Dysregulation of angiotensin II (Ang II) signaling, a major neurohumoral peptide acting mainly through angiotensin II type 1 receptors (AT1R), is involved in this response. Within cardiovascular control regions, including the paraventricular nucleus of the hypothalamus (PVN), nucleus tractus solitarius, and rostral ventrolateral medulla, exacerbated Ang II/AT1R signaling has been linked to oxidative stress, neuroinflammation, blood-brain barrier dysfunction, impaired reflex control, and sympathoexcitation. Here, the central question was whether endogenous mechanisms that normally restrain Ang II/AT1R signaling are altered during hypertension. Two candidates were studied. Nuclear factor erythroid 2-related factor 2 (Nrf2) was examined as a redox-sensitive pathway that may limit oxidative and inflammatory stress downstream of Ang II signaling. Angiotensin II type 1 receptor-associated protein (ATRAP) was examined as an AT1R-interacting protein positioned closer to receptor-level regulation. Experiments were performed in spontaneously hypertensive rats (SHR) and normotensive controls using cellular, molecular, and, in selected cases, functional approaches. In the Nrf2 studies, Nrf2 protein density was lower in the PVN of SHR, especially in astrocytes. This reduction was prevented by losartan but not hydralazine, despite similar blood pressure lowering, suggesting that PVN Nrf2 loss is more related to Ang II/AT1R signaling than to arterial pressure alone. Omaveloxolone did not reduce arterial pressure or restore baroreflex sensitivity in adult SHR, but reduced the exaggerated depressor response to ganglionic blockade, suggesting that Nrf2 activation may affect sympathetic blood pressure regulation. Agtrap/ATRAP expressions were also characterized in central cardiovascular regions. Agtrap mRNA and ATRAP protein density were selectively increased in the PVN of SHR, with no significant changes in the rostral ventrolateral medulla, supraoptic nucleus, or cortex. Further, although ATRAP immunoreactivity appeared most strongly associated with neuronal profiles, it was also detected in microglia and astrocytes. These findings indicate that hypertension is accompanied by altered endogenous regulation at more than one level of the central Ang II/AT1R pathway. Impaired PVN Nrf2 defense, especially in astrocytes, may leave Ang II-sensitive circuits more vulnerable to redox and inflammatory stress, while selective PVN ATRAP upregulation identifies a receptor-associated change that warrants future mechanistic study.