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Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis
Liu, Simeng Huang, Zhimin Tang, Anna Wu, Xiaoqing Aube, Jeffrey Xu, Liang Xing, Changying Huang, Yufeng
Liu, Simeng
Huang, Zhimin
Tang, Anna
Wu, Xiaoqing
Aube, Jeffrey
Xu, Liang
Xing, Changying
Huang, Yufeng
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Abstract
Recent identification of an RNA-binding protein (HuR) that regulates mRNA turnover and translation of numerous transcripts via binding to an ARE in their 3′-UTR involved in inflammation and is abnormally elevated in varied kidney diseases offers a novel target for the treatment of renal inflammation and subsequent fibrosis. Thus, we hypothesized that treatment with a selective inhibition of HuR function with a small molecule, KH-3, would down-regulate HuR-targeted proinflammatory transcripts thereby improving glomerulosclerosis in experimental nephritis, where glomerular cellular HuR is elevated. Three experimental groups included normal and diseased rats treated with or without KH-3. Disease was induced by the monoclonal anti-Thy 1.1 antibody. KH-3 was given via daily intraperitoneal injection from day 1 after disease induction to day 5 at the dose of 50 mg/kg BW/day. At day 6, diseased animals treated with KH-3 showed significant reduction in glomerular HuR levels, proteinuria, podocyte injury determined by ameliorated podocyte loss and podocin expression, glomerular staining for periodic acid-Schiff positive extracellular matrix proteins, fibronectin and collagen IV and mRNA and protein levels of profibrotic markers, compared with untreated disease rats. KH-3 treatment also reduced disease-induced increases in renal TGFβ1 and PAI-1 transcripts. Additionally, a marked increase in renal NF-κB-p65, Nox4, and glomerular macrophage cell infiltration observed in disease control group was largely reversed by KH-3 treatment. These results strongly support our hypothesis that down-regulation of HuR function with KH-3 has therapeutic potential for reversing glomerulosclerosis by reducing abundance of pro-inflammatory transcripts and related inflammation.
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Date
2020-06-18
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Portland Press
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Keywords
Inflammation, Renal fibrosis, RNA-binding protein
Citation
Liu, S., Huang, Z., Tang, A., Wu, X., Aube, J., Xu, L., Xing, C., & Huang, Y. (2020). Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis. Clinical science (London, England : 1979), 134(12), 1433–1448. https://doi.org/10.1042/CS20200193