MiR-92d-3p suppresses the progression of diabetic nephropathy renal fibrosis by inhibiting the C3/HMGB1/TGF-β1 pathway

Abstract

The pathogenesis of diabetic nephropathy (DN) has not been fully elucidated. MicroRNAs play an important role in the onset and development of DN renal fibrosis. Thus, this study aimed to investigate the effect of miR-92d-3p on the progression of DN renal fibrosis. We used qRT-PCR to detect the expression levels of miR-92d-3p in the kidneys of patients with DN. Then, after transfecting lentiviruses containing miR-92d-3p into the kidneys of a DN mouse model and HK-2 cell line, we used qRT-PCR to detect the expression levels of miR-92d-3p, C3, HMGB1, TGF-β1, α-SMA, E-cadherin, and Col Ⅰ. The expression levels of IL-1β, IL-6, and TNF-α in the HK-2 cells were detected through enzyme-linked immunosorbent assay, and Western blotting and immunofluorescence were used in detecting the expression levels of fibronectin, α-SMA, E-cadherin, and vimentin. Results showed that the expression levels of miR-92d-3p in the kidney tissues of patients with DN and DN animal model mice decreased, and C3 stimulated HK-2 cells to produce inflammatory cytokines. The C3/HMGB1/TGF-β1 pathway was activated, and EMT was induced in the HK-2 cells after human recombinant C3 and TGF-β1 protein were added. miR-92d-3p inhibited inflammatory factor production by C3 in the HK-2 cells and the activation of the C3/HMGB1/TGF-β1 pathway and EMT by C3 and TGF-β1. miR-92d-3p suppressed the progression of DN renal fibrosis by inhibiting the activation of the C3/HMGB1/TGF-β1 pathway and EMT.

β‐Amyrin ameliorates diabetic nephropathy in mice and regulates the miR‐181b‐5p/HMGB2 axis in high glucose‐stimulated HK‐2 cells

“…For example, HMGB1 is activated in mesangial cells under HG condition and DN patients 51 . MiR‐92d‐3p suppresses renal fibrosis and inflammation of HG‐stimulated HK‐2 cells by inhibiting the C3/HMGB1/TGF‐β1 pathway during DN progression 52 . Long noncoding RNA maternally expressed 3 (MEG3) exacerbates the hypoxia/reoxygenation‐stimulated HK‐2 cell apoptosis via the miR‐129‐5p/HMGB1 axis 53 .…”

Kidney microRNA Expression Pattern in Type 2 Diabetic Nephropathy in BTBR Ob/Ob Mice

“…Thus, miR-30a, miR-30c, miR-26a, miR-130, miR-23b, Let-7days, and miR-98 have shown to modulate EMT in experimental DN ( Bai et al, 2016 ; Liu et al, 2016 ; Zheng et al, 2016 ; Zhu et al, 2019 ; Gao et al, 2020 ; Wang Y. et al, 2021 ). Moreover, the anti-fibrotic effects of other miRNAs, including miR-200a, miR-455-3p, miR-92days-3p, miR-130b, miR-26a, and miR-29a, have been also described in DN ( Du et al, 2010 ; Wang et al, 2011 ; Lin et al, 2014 ; Koga et al, 2015 ; Bai et al, 2016 ; Wu et al, 2018 ; Zhang, 2021 ). Apart from miRNAs, other non-coding RNAs have been postulated to regulate gene expression in DN.…”

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

“…A so-called “C3/HMGB1/TGF-β1 pathway” was reported in two publications investigating the pathogenesis of diabetic nephropathy and its associated chronic renal fibrosis ( 46 , 47 ). In response to C3a stimulation (provided by macrophage infiltration into renal interstitial tissues), HMGB1 translocates from nucleus to cytoplasm in primary renal tubular epithelial cells, and expression of HMGB1 and its receptor TLR4 gradually increases in their cytoplasm from 24 to 48 h after C3a stimulation.…”

“…This will trigger epithelial to mesenchymal transition through the HMGB1/TLR4/p65/TGF-β1 signaling pathway ( 46 ). These effects have been inhibited by the grapefruit component GSPE ( 46 ) or the specific MiR-92d-3p miRNA in a renal tubular epithelial cell line (HK2) ( 47 ).…”