Interleukin‐17A Exacerbates the Development of High‐Salt‐Induced Hypercholesterolemia

This study aimed to investigate the molecular mechanisms through which dietary salt affects blood pressure and cholesterol homeostasis. We established a hypertension and hypercholesterolemia model via feeding a high salt diet (8% NaCl, HSD) to Dahl salt‐sensitive (SS) rats for 5 weeks. This diet regime successfully induced hypertension and increased serum TC and LDL‐C. RNA‐seq and RT‐qPCR analyses confirmed that activation of cholesterol biosynthesis in liver tissues by an HSD led to elevated serum cholesterol levels. In vivo experiments suggested that the HSD‐induced elevation of serum IL‐17 likely contributes to hypertension and dyslipidemia as a co‐pathogenic factor. Knockdown or overexpression of IL‐17RA in HepG2 cells and HUVECs further confirmed that upregulating this signaling pathway promotes the nuclear entry of SREBP2, a protein critical to cholesterol biosynthesis. In HUVECs, IL‐17RA inhibition enhanced NO production, whereas IL‐17RA overexpression suppressed it. Administration of rat‐specific anti‐IL‐17A antibody significantly attenuated salt‐induced hypertension and reduced serum TC and LDL‐C levels. These findings demonstrate that a high‐salt diet elevates the risk of hypertension and hypercholesterolemia by activating IL‐17 signaling pathway. This suggests that IL‐17A inhibitors may serve as potential therapeutic agents for treating salt‐induced hypertension and hypercholesterolemia.