CircSMAD4 alleviates high glucose-induced inflammation, extracellular matrix deposition and apoptosis in mouse glomerulus mesangial cells by relieving miR-377-3p-mediated BMP7 inhibition

Rina Wu; Zheli Niu; Guangwei Ren; Lin Ruan; Lijun Sun

doi:10.1186/s13098-021-00753-1

CircSMAD4 alleviates high glucose-induced inflammation, extracellular matrix deposition and apoptosis in mouse glomerulus mesangial cells by relieving miR-377-3p-mediated BMP7 inhibition

Diabetol Metab Syndr. 2021 Nov 20;13(1):137. doi: 10.1186/s13098-021-00753-1.

Authors

Rina Wu¹, Zheli Niu², Guangwei Ren², Lin Ruan², Lijun Sun³

Affiliations

¹ Department of Endocrinology, Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao, China.
² Department of Nephrology, The First Hospital of Hebei Medical University, 9 Donggang Road, Shijiazhuang City, 050030, Hebei Province, China.
³ Department of Nephrology, The First Hospital of Hebei Medical University, 9 Donggang Road, Shijiazhuang City, 050030, Hebei Province, China. docsunlj89@163.com.

Abstract

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus. Accumulating studies suggest that the deregulation of circular RNA (circRNA) is involved in DN pathogenesis. This study aimed to investigate the role of circSMAD4 in DN models.

Methods: Mice were treated with streptozotocin to establish DN models in vivo. Mouse glomerulus mesangial cells (SV40-MES13) were treated with high glucose to establish DN models in vitro. The expression of circSMAD4, miR-377-3p and bone morphogenetic protein 7 (BMP7) mRNA was measured by quantitative real-time PCR (qPCR). The releases of inflammatory factors were examined by ELISA. The protein levels of fibrosis-related markers, apoptosis-related markers and BMP7 were checked by western blot. Cell apoptosis was monitored by flow cytometry assay. The predicted relationship between miR-377-3p and circSMAD4 or BMP7 was validated by dual-luciferase reporter assay or pull-down assay.

Results: CircSMAD4 was poorly expressed in DN mice and HG-treated SV40-MES13 cells. HG induced SV40-MES13 cell inflammation, extracellular matrix (ECM) deposition and apoptosis. CircSMAD4 overexpression alleviated, while circSMAD4 knockdown aggravated HG-induced SV40-MES13 cell injuries. MiR-377-3p was targeted by circSMAD4, and miR-377-3p enrichment partly reversed the effects of circSMAD4 overexpression. BMP7 was a target of miR-377-3p, and circSMAD4 regulated BMP7 expression by targeting miR-377-3p. MiR-377-3p overexpression aggravated HG-induced injuries by suppressing BMP7.

Conclusion: CircSMAD4 alleviates HG-induced SV40-MES13 cell inflammation, ECM deposition and apoptosis by relieving miR-377-3p-mediated inhibition on BMP7 in DN progression.

Keywords: BMP7; Diabetic nephropathy; circSMAD4; miR-377-3p.