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.