Journal Article

Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling

Han, Yue, Xu, Jiaxi, Wang, Jiawei, Yuan, Miao, Yuan, Shenglan, Wang, Yi, Chen, Xingjuan, Sun, Qi, Yang, Rui, Yang, Ruijie, Mu, Junya, Wu, Hanxue, Li, Fanni, Xiao, Lei, Qiu, Zihan, Zhang, Ming

2025

Overview

Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 ( GluT1 ) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen ( Agt ) expression was markedly upregulated in most astrocytes, together with neuronal expression of Agtr1a . In cultured neuronal cells, angiotensin II (ang II) elevated mitochondrial membrane potential and ATP biosynthesis. In mice with neuronal AT 1a R knockout (AT1N), DOCA-salt failed to induce cognitive impairment. Additionally, DOCA-salt-associated reduction of acetylcholine, accumulation of p-Tau, and upregulation of lysine succinylation were not observed in AT1N mice. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME. Our data provide evidence that hypertension induced metabolic rearrangement (enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation) in the neuro-vascular unit, due to downregulated glucose uptake in ECs. Increased neuronal energy consumption, via local ang II/AT 1 R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations. Together, by multi-omics analysis, this study provided novel insights regarding how hypertension increases the risk for age-related cognitive impairment. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acetic acid / Age / Alzheimer's disease / Angiotensin / Angiotensin II / Angiotensinogen / Antihypertensives / Astrocytes / Biomedical and Life Sciences / Biomedicine / Blood flow / Blood levels / Brain / Cellular signal transduction / Cerebral blood flow / Cerebral cortex / Cognitive ability / Complications and side effects / Degeneration / Down-regulation / Endothelial cells / Energy metabolism / Energy shortages / Enzymes / Functional magnetic resonance imaging / Glucose / Health aspects / Hospitals / Hypertension / Immunology / Kidney diseases / Laboratory animals / Lysine / Membrane potential / Metabolic regulation / Metabolic reprogramming / Metabolism / Mitochondria / Nervous system / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neuroinflammation and Cellular Metabolism / Neurology / Neurons / Neurosciences / Norepinephrine / Oxidative stress / Pathogenesis / Phenotypes / Standard scores / Statistical analysis / Substance abuse treatment / Tricarboxylic acid cycle