CircUBXN7 promotes macrophage infiltration and renal fibrosis associated with the IGF2BP2-dependent SP1 mRNA stability in diabetic kidney disease

Ziyue Lin; Dan Lv; Xiaohui Liao; Rui Peng; Handeng Liu; Tianhui Wu; Keqian Wu; Yan Sun; Zheng Zhang

doi:10.3389/fimmu.2023.1226962

CircUBXN7 promotes macrophage infiltration and renal fibrosis associated with the IGF2BP2-dependent SP1 mRNA stability in diabetic kidney disease

Front Immunol. 2023 Sep 6:14:1226962. doi: 10.3389/fimmu.2023.1226962. eCollection 2023.

Authors

Ziyue Lin^{1

2}, Dan Lv^{1

2}, Xiaohui Liao¹, Rui Peng³, Handeng Liu⁴, Tianhui Wu², Keqian Wu², Yan Sun^{1

2}, Zheng Zhang^{1

2}

Affiliations

¹ Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, China.
³ Department of Bioinformatics, Chongqing Medical University, Chongqing, China.
⁴ Center of Teaching and Learning, Chongqing Medical University, Chongqing, China.

Abstract

Introduction: Inflammatory cell infiltration is a novel hallmark of diabetic kidney disease (DKD), in part, by activated macrophages. Macrophage-to-tubular epithelial cell communication may play an important role in renal fibrosis. Circular RNAs (circRNAs) have been reported in the pathogenesis of various human diseases involving macrophages activation, including DKD. However, the exact mechanism of circRNAs in macrophage infiltration and renal fibrosis of DKD remains obscure.

Methods: In our study, a novel circRNA circUBXN7 was identified in DKD patients using microarray. The function of circUBXN7 in vitro and in vivo was investigated by qRT-PCR, western blot, and immunofluorescence. Finally, a dual-luciferase reporter assay, ChIP, RNA pull-down, RNA immunoprecipitation and rescue experiments were performed to investigate the mechanism of circUBXN7.

Results: We demonstrated that the expression of circUBXN7 was significantly upregulated in the plasma of DKD patients and correlated with renal function, which might serve as an independent biomarker for DKD patients. According to investigations, ectopic expression of circUBXN7 promoted macrophage activation, EMT and fibrosis in vitro, and increased macrophage infiltration, EMT, fibrosis and proteinuria in vivo. Mechanistically, circUBXN7 was transcriptionally upregulated by transcription factor SP1 and could reciprocally promote SP1 mRNA stability and activation via directly binding to the m6A-reader IGF2BP2 in DKD.

Conclusion: CircUBXN7 is highly expressed in DKD patients may provide the potential biomarker and therapeutic target for DKD.

Keywords: CircUBXN7; IGF2BP2; diabetic kidney disease; epithelial-mesenchymal transition; macrophage infiltration; tubulointerstitial fibrosis.

Publication types

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

MeSH terms

Biological Assay
Diabetes Mellitus*
Diabetic Nephropathies* / genetics
Fibrosis
Humans
Macrophages
RNA, Circular* / genetics
RNA-Binding Proteins / genetics

Substances

IGF2BP2 protein, human
RNA, Circular
RNA-Binding Proteins
UBXN7 protein, human
SP1 protein, human

Grants and funding

This study was funded by the National Natural Science Foundations of China (No. 82270876 and 81970702), the Science and Technology Research Program of Chongqing Municipal Education Commission (CSTB2022NSCQ-MSX0126) and CQMU program for youth innovation in future medicine (w0173).