Inhibition of ALKBH5 inhibits inflammation and excessive proliferation by promoting TRIM13 m6A modifications in glomerular mesangial cells

Naunyn-Schmiedeberg's Archives of Pharmacology(2024)

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Abstract
Chronic glomerulonephritis (CGN) refers to the inflammation of glomeruli in the kidneys. Glomerular mesangial cells (GMCs) play a pivotal role in the development of CGN. In the present study, we investigated the impact of ALKBH5, a m6A demethylase, on inflammation and hyperproliferation in mouse glomerular mesangial cells (MMCs) and elucidated the molecular mechanisms contributing to CGN. Western blotting and reverse transcriptase-polymerase chain reaction (RT-qPCR) were employed to evaluate the expression of ALKBH5 and TRIM13. In addition, enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of inflammatory factors (IL-1β, TNF-α, and IL-10) in the lipopolysaccharide (LPS)-induced MMCs supernatant. Methylated RNA immunoprecipitation (MeRIP) was performed to investigate the effect of ALKBH5 on the levels of TRIM13-m6A mRNA. The stability of TRIM13 mRNA was evaluated using an actinomycin D assay. Significantly elevated expression of ALKBH5 was found in LPS-induced MMCs. Interference with ALKBH5 expression inhibited inflammation and excessive proliferation in LPS-induced MMCs. Moreover, interfering with ALKBH5 expression significantly reduced the levels of TRIM13-m6A modification. The overexpression of TRIM13 in MMCs reversed the inflammation and proliferation induced by ALKBH5 interference. In addition, interference with TRIM13 expression inhibited the activation of the NF-κB pathway and suppressed inflammation and proliferation in MMCs. Inhibiting ALKBH5 hinders inflammation and hyperproliferation by improving TRIM13-m6A modification in glomerular MCs. We believe these findings will further provide insights into the molecular mechanisms and potential therapeutic targets for CGN.
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Key words
Chronic glomerulonephritis,Glomerular mesangial cells,m6A modification,ALKBH5,TRIM13
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