MiR-429 influences the development of systemic lupus erythematosus nephritis by targeting SORT1

Abstract

Purpose

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune dysregulation, inflammation, and organ damage, particularly affecting the kidneys. This study aimed to investigate the role of miR-429 and its target gene SORT1 in the pathogenesis of SLE, focusing on their effects on immune cell balance, inflammation, and kidney injury.

Methods

Differential expression of miRNAs in SLE and lupus nephritis (LN) was analyzed using the GEO database, with identifying miR-429 as a potential regulator. In vitro, human mesangial cells (HMCs) were treated with TGF-β1 to investigate the effects of miR-429 and SORT1 on HMCs function in SLE. In vivo, a MRL/lpr mice were used as an SLE model to assess the impact of miR-429 on immune cell populations, inflammatory cytokine levels, and kidney pathology. Various assays, including qPCR, flow cytometry, CCK-8, and histological staining, were employed to evaluate gene expression, cell proliferation, and tissue damage.

Results

miR-429 was downregulated in SLE patients and identified as a regulator of SORT1. In vitro, miR-429 expression decreased while SORT1 expression increased in TGF-β1-treated HMCs. Overexpression of miR-429 inhibited HMCs proliferation and reduced levels of IL-1β, IL-6, and TNF-α; however, these effect were reversed by SORT1 overexpression. In vivo, miR-429 treatment alleviated kidney damage in SLE mice, decreased levels of inflammatory cytokines, urinary albumin, uACR, SCr, and BUN, increased levels of Nephrin, Podocin, and WT1, and improved kidney histology. Conversely, co-overexpression of miR-429 and SORT1 attenuated these protective effects. Furthermore, miR-429 overexpression restored the balance between Th17 and Treg cells in SLE mice, whereas SORT1 overexpression suppressed this restoration.

Conclusion

miR-429 targets SORT1 to modulate immune responses, reduce inflammation, and protect against kidney damage in SLE, suggesting that targeting the miR-429/SORT1 axis may offer a promising therapeutic strategy for SLE.