Mechanism of AGT-Mediated Magnesium Ion Uptake in Age-Related Olfactory Dysfunction

BACKGROUND: Ageing is associated with a significant decline in olfactory function, though the underlying mechanisms remain unclear. Angiotensinogen (AGT) participates in multiple cellular processes, including inflammation, oxidative stress (OS), and magnesium (Mg²⁺) homeostasis. In this study, we investigated how decreased AGT expression in olfactory epithelial cells affects Mg²⁺ uptake, inflammation, oxidative stress, and mitochondrial apoptosis, ultimately contributing to olfactory dysfunction. METHODS: Rapidly ageing male senescence-accelerated mouse prone 6 (SAMP6) mice and age-matched normal senescence accelerated mouse resistant 1 (SAMR1) control mice were used to evaluate olfactory function via the buried food test. Blood and olfactory epithelium tissues were collected for biochemical analyses. Mouse olfactory epithelial (MOE) cells were cultured, and AGT expression was knocked down, with or without MgSO₄ supplementation. Mitochondrial membrane potential (Δψm) was assessed using JC-1 staining, and cell viability was measured via Cell Counting Kit-8 (CCK-8) assay. RESULTS: SAMP6 mice exhibited impaired olfactory function, with significant structural damage to the olfactory epithelium and reduced expression of olfactory marker protein (OMP, p < 0.05). Elevated expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), reactive oxygen species (ROS), Bcl-2-associated X protein (Bax), caspase-3, and caspase-9 was observed in blood and olfactory epithelium tissues, while levels of AGT, Angiotensin II (Ang II), Mg²⁺, and the Mg²⁺ transporter mitochondrial RNA splicing 2 protein (MRS2) and transient receptor potential cation channel subfamily M member 6 (TRPM6) were significantly decreased (p < 0.05). In vitro, AGT knockdown reduced viability and Δψm in MOE cells (p < 0.05), elevated IL-1β, TNF-α and ROS (p < 0.05), and suppressed the expression of AGT, Ang II, MRS2, and TRPM6 (p < 0.05). Notably, MgSO₄ administration partially reversed the effects of AGT knockdown on MOE cells (p < 0.05). CONCLUSION: Reduced AGT expression in olfactory epithelial cells impairs Mg²⁺ uptake, leading to inflammation, oxidative stress, and mitochondrial apoptosis, ultimately contributing to age-related olfactory dysfunction. Our findings suggest that targeting AGT or Mg²⁺ homeostasis may offer promising therapeutic strategies for age-related olfactory disorders.