Changhao Wu

Neurogenic hypertension is characterized by sustained sympathetic activation arising from dysregulation within the central autonomic network. The rostral ventrolateral medulla (RVLM) is a major sympathetic premotor region that integrates reflex, neurohumoral, inflammatory, and metabolic signals. Oxidative stress within the RVLM can increase neuronal excitability, enhance glutamatergic transmission, weaken nitric oxide-dependent GABAergic inhibition, and promote sympathetic activation. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species in this region. Direct anatomical evidence is the strongest for components of the NADPH oxidase 2 (NOX2) complex, whereas the cellular distribution and functional roles of Nox1, Nox4, and other isoforms remain less clearly defined. Current evidence more strongly supports RVLM Nox-related oxidative stress as a mechanism that amplifies and maintains established hypertension than as an independent initiator of chronic hypertension. Sex and ovarian hormone status modulate these redox and autonomic mechanisms. Estrogen signaling can influence neuronal excitability, inflammation, and oxidative balance, but its effects depend on receptor subtype, endocrine state, exposure pattern, age, and hypertensive background. Estradiol replacement after ovarian hormone loss may reduce RVLM oxidative stress, whereas prolonged exposure in intact cycling animals may increase superoxide production and Nox-related gene expression. Human studies also associate menopause with altered blood pressure, arterial stiffness, sympathetic activity, and baroreflex regulation, although direct evidence for estrogen receptor and Nox signaling within the human RVLM remains lacking. This review summarizes current evidence and highlights priorities for mechanistic and translational research.

Patients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca²⁺ overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes cytosolic Ca²⁺ rise and the specific mechanism whereby overloaded Ca²⁺ induces ferroptosis remain unknown. The purpose of our study was to explore the role of IP3R-dependent mitochondrial dysfunction in C5b-9 mediated ferroptosis in trichloroethylene sensitized kidney. Our results showed that IP3R was activated, and mitochondrial membrane potential was decreased in the renal epithelial cells of trichloroethylene-sensitized mice, and these changes were antagonized by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was reproduced in a C5b-9-attacked HK-2 cell model. Further investigation showed that RNA interference with IP3R not only alleviated C5b-9-induced cytosolic Ca²⁺ overload and mitochondrial membrane potential loss but also attenuated C5b-9-induced ferroptosis in HK-2 cells. Mechanistically, IP3R-dependent cytosolic Ca²⁺ overload activated the mitochondrial permeability transition pore, resulting in the loss of mitochondrial membrane potential and ferroptosis of HK-2 cells. Finally, cyclosporin A, a mitochondrial permeability transition pore inhibitor, not only ameliorated IP3R-dependent mitochondrial dysfunction but also blocked C5b-9-induced ferroptosis. Taken together, these results suggest that IP3R-dependent mitochondrial dysfunction plays an important role in trichloroethylene sensitized renal tubular ferroptosis.