Vaccine Against PCSK9 Improved Renal Fibrosis by Regulating Fatty Acid β‐Oxidation

Abstract

Background Defects in the renal fatty acid β‐oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qβ‐003. In this study, we investigated the potential effectiveness of the PCSK9Qβ‐003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low‐density lipoprotein receptor+/− male mice fed with a high‐cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate‐buffered saline group, the Qβ virus‐like particles group and the PCSK9Qβ‐003 vaccine group. Mice of the PCSK9Qβ‐003 group were injected with the PCSK9Qβ‐003 vaccine (100 μg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N‐nitro‐l‐arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qβ‐003 vaccine obviously decreased total cholesterol and low‐density lipoprotein cholesterol in low‐density lipoprotein receptor+/− mice with hypercholesterolemia. Compared with the phosphate‐buffered saline and Qβ virus‐like particles groups, the PCSK9Qβ‐003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qβ‐003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qβ‐003 vaccine obviously upregulated the expression of low‐density lipoprotein receptor, very‐low‐density lipoprotein receptor, sterol‐regulatory element binding protein 2, and fatty acid β‐oxidation–related factors, and ameliorated renal fibrosis‐related molecules both in the unilateral ureteral obstruction and N‐nitro‐l‐arginine methyl ester models. Conclusions This study suggested that the PCSK9Qβ‐003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid β‐oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.

Keywords

• fatty acid β‐oxidation
• hyperlipidemia
• proprotein convertase subtilisin/kexin type 9
• renal fibrosis
• vaccine