NF-κB p65 mediated lnc-Traf3ip2 exacerbates renal fibrosis in diabetic kidney disease.

Abstract

Aims: Diabetic kidney disease (DKD) is the predominant type of end-stage renal disease. The fibrotic response in glomerular mesangial cells (MCs) acts as an initial injury during DKD progression, but the molecular mechanism remains to be explored. Here, this present study aimed to investigate the role of NF-κB p65 mediated long noncoding RNA (lncRNA) lnc-Traf3ip2 in renal fibrosis and DKD progression.

Methods: The different expressions of lncRNAs in renal tissues of db/db DKD mice (n = 3) and db/dm controls (n = 3) were screened by scRNA-seq and RNA-seq. Plasma of DKD patients (n = 40) and renal tissues of DKD mice (n = 35) and their controls were further used to examine the expressions of lnc-Traf3ip2. Moreover, the relationship between the expression of lnc-Traf3ip2 and indexes of kidney function was also analyzed by Pearson correlation coefficient analysis. Furthermore, the biological functions of lnc-Traf3ip2 in mesangial cell fibrosis and renal injury were investigated by qRT-PCR, western blot and immunofluorescence in DKD in vivo and in vitro. Finally, the dual-luciferase reporter assay and ChIP were performed to investigate the regulatory mechanism of lnc-Traf3ip2 transcription.

Results: In our study, the results of scRNA-seq, RNA-seq and qRT-PCR revealed that lnc-Traf3ip2, which was highly expressed in mesangial cells and upregulated in renal tissues of DKD mice and the plasma of DKD patients. Data also showed lnc-Traf3ip2 was positively correlated with UACR in DKD. Moreover, overexpression of lnc-Traf3ip2 could promote fibrosis of MCs in vitro, whereas silencing lnc-Traf3ip2 alleviated MCs fibrosis under high glucose condition. Additionally, lnc-Traf3ip2 knockdown alleviated renal fibrosis in DKD mice. Mechanistically, transcription factor NF-κB subunit p65 could promote the expression of lnc-Traf3ip2 via directly binding to the promoter of lnc-Traf3ip2.

Conclusions: Taken together, our data suggest the role of lnc-Traf3ip2 in fibrogenic factor in DKD induced by transcription factor NF-κB p65 and identified it as an therapeutic target for DKD.