Low-Grade Type I Interferon Activation Protects Against Hypertension Target-Organ Damage in a Susceptible Murine Model

Objective: Hypertension (HTN) affects small vessels in multiple organs (brain, kidney, heart, retina), causing severe microvascular damage. HTN-related target-organ injury cannot be explained solely by blood pressure (BP), indicating individual susceptibility mechanisms. Although inflammation is classically considered deleterious in HTN, its precise role in hypertensive microvascular injury remains unclear. To address this gap, we developed a murine model enabling systematic assessment of HTN-related target-organ damage.Design and method: Three-month-old 129S1/SvImJ (129/Sv) and C57BL/6J mice were treated with angiotensin II (AngII; 600 ng/kg/min) or saline for 4 weeks under identical breeding, housing, and environmental conditions. Vascular injury was assessed in the brain, heart, kidneys, and retina. In hypertensive 129/Sv mice, low-grade inflammation was induced using weekly low-dose lipopolysaccharide (LPS, 0.25 mg/kg, i.p.) or pharmacological activation of the cGAS-STING/type I interferon (IFN-I) pathway with the murine STING agonist DMXAA (1 mg/kg, i.p., weekly). Complementary experiments were conducted in IFNAR1-deficient C57BL/6J mice to assess the causal role of IFN-I signaling. Results: Both strains developed comparable AngII-induced HTN, but only hypertensive 129/Sv mice exhibited diffuse HTN target-organ microvascular damage (Figure 1). Transcriptomic analysis of brain microvessels revealed a selective and paradoxical downregulation of the cGAS–STING/type I interferon signaling pathway in susceptible 129/Sv mice, compared with resistant C57BL/6J mice, which showed early activation of brain tissue-resident microglia (IBA1). Specific agonist of INF-1 pathway (DMXAA intra peritoneal infusion) reactivated IFN-I signaling, reduced albuminuria, improved renal function, attenuated blood–brain barrier hyperpermeability, and prevented left ventricular hypertrophy without decreasing BP (Figure 2). IFNAR1-deficient C57BL/6J mice developed HTN-induced renal and cardiac injury, including albuminuria and hypertrophic cardiomyopathy. Conclusions: Using a murine model of HTN with identical BP but divergent outcomes, we show that repression of the cGAS–STING/type I interferon pathway underlies susceptibility to microvascular injury. Conversely, low-grade IFN-I activation confers a paradoxical, BP-independent protective effect on the kidney, brain, and heart. These findings challenge the traditional view of inflammation in HTN and support immunomodulatory strategies targeting IFN-I signaling to prevent organ damage.