Therapeutic DNA vaccine encoding CEMIP (KIAA1199) ameliorates kidney fibrosis in obesity through inhibiting the Wnt/β-catenin pathway

Chao-Hung Chen; Guan-Ming Ke; Pi-Chen Lin; Kun-Der Lin

doi:10.1016/j.bbagen.2021.130019

Therapeutic DNA vaccine encoding CEMIP (KIAA1199) ameliorates kidney fibrosis in obesity through inhibiting the Wnt/β-catenin pathway

Biochim Biophys Acta Gen Subj. 2021 Dec;1865(12):130019. doi: 10.1016/j.bbagen.2021.130019. Epub 2021 Sep 25.

Authors

Chao-Hung Chen¹, Guan-Ming Ke², Pi-Chen Lin³, Kun-Der Lin⁴

Affiliations

¹ General Research Service Center, National Pingtung University of Science and Technology, Pingtung, Taiwan; Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan; Division of Endocrinology and Metabolism, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan.
³ Division of Endocrinology and Metabolism, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Division of Endocrinology and Metabolism, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.. Electronic address: 890073@ms.kmuh.org.tw.

PMID: 34582938
DOI: 10.1016/j.bbagen.2021.130019

Abstract

Background: CEMIP is a novel risk factor of various cancers through activating Wnt/β-catenin /epithelial-mesenchymal transition between epithelial cells and stroma. The chronic fibrosis commonly contributes renal carcinogenesis in patients with obesity. As there have very few choices of medicines targeting CEMIP. This study intended to design therapeutic DNA vaccines for nephropathy in obesity, through diminishing the CEMIP/Wnt1/β-catenin pathway.

Method: In an 8-week experiment, plasmid-encoding CEMIP was vaccinated into high-fat diet (HFD) or obesity mice in the first 4 weeks, and then vaccination was stopped for at least 4 weeks. Then, plasma and spleens were harvested to evaluate anti-CEMIP antibody synthesis and T-helper type 1 and 2 activation after vaccination. Kidneys were collected to investigate efficacy of CEMIP DNA vaccine on inhibiting HFD and obesity-induced fibrosis and Wnt1/β-catenin pathway. To confirm that CEMIP crucially contributed towards fibrotic formation, CEMIP gene or siRNA transfection was performed in HK-2 cells under VLDL stimulation, or not.

Results: At the end point, anti-CEMIP antibody was successfully produced in the pcDNA 3.1-CEMIP vaccinated group, while Wnt1/β-catenin signaling and fibrosis was inactive. Through VLDL stimulation and CEMIP overexpression, Wnt1/β-catenin signaling and fibrosis significantly presented in vitro. Otherwise, anti-sera of CEMIP-vaccinated mice could inhibit the VLDL-induced Wnt1/β-catenin/fibrosis pathway in HK-2 cells. Similarly, the silencing of CEMIP by siRNA ameliorated the Wnt1/β-catenin pathway and fibrogenesis under VLDL stimulation.

Conclusion: DNA vaccine targeting CEMIP/Wnt1/β-catenin pathway plays a novel strategy in nephropathy.

General significance: Immune therapy might provide a new therapeutic option on nephropathy of obesity.

Keywords: CEMIP; DNA vaccine; Fibrosis; Nephropathy; Obesity; Wnt; β-Catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Male
beta Catenin*

Substances

CTNNB1 protein, human
beta Catenin