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.