Effect of auto anti-double stranded DNA on mesangial cells microrna profiles

Abstract

Autoantibodies-mediated inflammation at the resident kidney cells is crucial in the lupus nephritis (LN) pathogenesis. The objective of this study is to investigate the role of miRNA in human mesangial cells (HMCs) stimulated with auto anti-dsDNA IgG antibodies. The cells were treated with antibodies purified from active LN patients or non-specific IgG controls in the present of normal serum. The aberrant miRNA was screened using high throughput sequencing. Results showed that anti-dsDNA IgG upregulated 103 miRNAs and down-regulated 20 miRNAs which regulate genes in the cell cycle, catabolic process, regulation of transcription and apoptosis signaling. The miR-10a, which was listed in the top ten high abundance miRNA in HMCs, was specifically downregulated upon anti-dsDNA IgG induction. Interestingly, the expressions of miR-10a in kidney biopsy from LN patients (n=29) were downregulated compared to cadaveric donor kidney (n=6). The downregulation was correlated with proteinuria, which is the earliest sign of renal defect (r2 = 0.5266, p-value = 0.0115). Functional studies highlight the downstream regulator of miR-10a in the chemokine signaling and cell proliferation or apoptosis pathway. The luciferase assay confirmed for the first time that IL-8 was a direct target of miR-10a in HMCs. In conclusion, anti-dsDNA IgG Ab down-regulated miR-10a expression in HMC resulting in the induction of various target genes involved in HMCs proliferation and chemokine expression. Manipulation of miR-10a might be a new option for targeted therapy for LN.