Inhibition of RNA-binding protein HuR reduces glomerulosclerosis in experimental nephritis

• Published in: Clinical science (1979) Vol. 134; no. 12; pp. 1433 - 1448
• Main Authors: Liu, Simeng, Huang, Zhimin, Tang, Anna, Wu, Xiaoqing, Aube, Jeffrey, Xu, Liang, Xing, Changying, Huang, Yufeng
• Format: Journal Article
• Language: English
• Published: England 26.06.2020
• Subjects: Animals; Biomarkers - metabolism; Body Weight; Cell Polarity; Collagen - genetics; Collagen - metabolism; ELAV-Like Protein 1 - antagonists & inhibitors; ELAV-Like Protein 1 - metabolism; Extracellular Matrix - metabolism; Fibronectins - genetics; Fibronectins - metabolism; Fibrosis; Humans; Inflammation - pathology; Kidney Function Tests; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidney Glomerulus - physiopathology; Macrophages - metabolism; Male; Monocytes - metabolism; NADPH Oxidase 4 - metabolism; Nephritis - metabolism; Nephritis - pathology; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thy-1 Antigens; Transcription Factor RelA - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; renal fibrosis; inflammation; RNA-binding protein
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20200193

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.