Open AccessVaccine Against PCSK9 Improved Renal Fibrosis by Regulating Fatty Acid β‐Oxidation
Author(s) -
Wu Danyu,
Zhou Yanzhao,
Pan Yajie,
Li Chang,
Wang Yingxuan,
Chen Fen,
Chen Xiao,
Yang Shijun,
Zhou Zihua,
Liao Yuhua,
Qiu Zhihua
Publication year - 2020
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.119.014358
Subject(s) - medicine , endocrinology , kexin , low density lipoprotein , lipoprotein , renal function , ldl receptor , cholesterol
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 PCSK 9 (proprotein convertase subtilisin/kexin type 9), named PCSK 9Qβ‐003. In this study, we investigated the potential effectiveness of the PCSK 9Qβ‐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 PCSK 9Qβ‐003 vaccine group. Mice of the PCSK 9Qβ‐003 group were injected with the PCSK 9Qβ‐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 PCSK 9Qβ‐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 PCSK 9Qβ‐003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK 9Qβ‐003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK 9Qβ‐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 PCSK 9Qβ‐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.