Abstract: TH-PO0255
High Salt-Induced Mitochondrial Dysfunction Mediates Salt-Sensitive Hypertension and Renal Injury via the MR/RUNX1 Pathway
Session Information
- Hypertension and CVD: Mechanisms
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Zhang, Xi, Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shannxi Province, China
- Feng, Zhaode, Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi’an, Shannxi Province, China
- Mu, Jianjun, Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shannxi Province, China
Background
Excessive salt intake is a major risk factor for hypertension and chronic kidney disease. Runt-related transcription factor 1 (RUNX1) was upregulated in the kidneys of high-salt-fed Dahl salt-sensitive (DSS) rats via transcriptomic analysis. However, the mechanisms by which RUNX1 mediates high-salt-induced renal injury remain unclear.
Methods
DSS rats were fed a normal-salt, high-salt, or high-salt plus finerenone (a mineralocorticoid receptor [MR] antagonist) diet. Renal tissues were then collected for RNA-seq analysis. Human proximal tubular epithelial (HK-2) cells were subjected to RUNX1 knockdown or overexpression to elucidate the molecular mechanisms by which RUNX1 mediates renal injury.
Results
High-salt feeding activated renal MR and upregulated RUNX1, along with severe mitochondrial damage and hypertension, which was reversed by finerenone intervention. GWAS analysis revealed that RUNX1 maps to the risk locus associated with mitochondrial DNA (mtDNA), and Genebridge analysis showed a significant negative correlation between RUNX1 expression and mitochondrial-related pathways. In HK-2 cells, RUNX1 knockdown ameliorated high-salt-induced mitochondrial dysregulation, membrane potential depolarization, and mtDNA release, while overexpression exacerbated inflammatory responses and epithelial-mesenchymal transition. Mechanistically, high salt induced RUNX1-dependent mtDNA leakage into the cytoplasm, triggering cyclic GMP-AMP synthase (cGAS)-mediated stimulator of interferon genes (STING) pathway activation.
Conclusion
This study identified RUNX1-mediated mtDNA release and cGAS-STING pathway activation as central mechanisms driving renal injury. Targeting this axis may offer novel therapeutic strategies for salt-sensitive renal injury.
Funding
- Government Support – Non-U.S.