High salt activates the mineralocorticoid receptor-RUNX1 axis to mediate renal injury via mitochondrial dysfunction

Background Excessive salt intake contributes to salt-sensitive hypertension and renal injury in part through aberrant activation of the mineralocorticoid receptor (MR). While mitochondrial dysfunction is increasingly implicated in salt-induced target-organ damage, the transcriptional mechanisms linking MR overactivation to mitochondrial impairment remain unclear. By integrating cross-species transcriptomics with human genome-wide association study (GWAS) data, we sought to uncover potential pathogenic mediators contributing to salt-sensitive renal injury. Methods Kidney transcriptomic data from Dahl salt-sensitive (DSS) rats, DOCA-salt rats, and human hypertensive nephropathy were integrated with human GWAS and GeneBridge renal transcriptomic resources to prioritize renal injury-associated mediators. Human renal tubular epithelial (HK-2) cells were then exposed to high-salt conditions to model tubular injury and functionally assess Runt-related transcription factor 1 (RUNX1) as a prioritized candidate mediator. Luciferase reporter assays and genetic manipulations were performed to elucidate the transcriptional mechanisms coupling MR activation to mitochondrial dysfunction. Pharmacological interventions with the MR antagonist finerenone and the RUNX1 inhibitor Ro5-3335 were further conducted in high-salt-fed DSS rats to evaluate the translational potential of this pathogenic cascade. Results Integrative genomic analysis identified RUNX1 as a conserved candidate mediator markedly upregulated in salt-sensitive renal injury. Mechanistically, high-salt stimulation promoted MR-dependent RUNX1 transcriptional activation. Aberrant RUNX1 upregulation contributed to mitochondrial damage and cytosolic mitochondrial DNA (mtDNA) release, which in turn engaged the cGAS-STING innate immune pathway and promoted renal tubular inflammatory responses and tubulointerstitial fibrosis. Genetic knockdown of RUNX1 attenuated these mitochondrial and inflammatory alterations, whereas RUNX1 overexpression exacerbated them. The MR antagonist finerenone exerted significant renoprotective effects by suppressing MR-RUNX1 signaling and downstream mitochondrial and inflammatory injury. Furthermore, in vivo pharmacological inhibition of RUNX1 with Ro5-3335 effectively attenuated mitochondrial dysfunction and renal pathological damage, supporting RUNX1 as a therapeutically relevant mediator. Conclusions Our study identifies RUNX1 as an important transcriptional mediator linking aberrant MR signaling to mitochondrial dysfunction, inflammatory activation, and fibrotic remodeling. Targeting the MR-RUNX1 axis represents a promising therapeutic strategy for mitigating salt-sensitive hypertension and renal injury.