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

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.

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

“…Additionally, Human Antigen R (HuR) also known with its alternative name ELAVL1, is a ubiquitously expressed RBP, which is upregulated and activated under high glucose and in diabetes [ 14 ]. HuR binds to specific domains known as AU-rich elements (ARE) in the 3′UTRs of target genes that play a role in inflammation and diabetic nephropathy [ 15 , 16 , 17 ]. Once it is activated, it translocates to the cytoplasm to bind its mRNA targets affecting their stability and translation [ 18 ].…”

Sublytic C5b-9 Induces CCL3/4 Production and Macrophage Accumulation in Thy-1N Rats via PKC-α/p65/IRF-8 Axis

“…C5b-9 formation), Mφ infiltration, pro-inflammatory cytokine and chemokine production all contribute to the renal pathological changes of MsPGN 1 - 3 , 6 , 34 - 36 . As a well-established animal model of MsPGN, Thy-1N pathogenesis is dependent on complement particularly sublytic C5b-9 8 - 12 . Our previous studies have revealed that the production of some pro-inflammatory cytokines and chemokines including IL-6, IL-23, IL-36α, MCP-1 and RANTES was obviously increased in the renal tissues of Thy-1N rats and in the GMCs exposed to sublytic C5b-9 13 - 15 .…”

“…Rat Thy-1 nephritis (Thy-1N) is an animal model for studying MsPGN 8 - 10 . Similar to human MsPGN, Thy-1N undergoes complement activation and a series of pathological changes including renal inflammation, GMC proliferation and ECM accumulation.…”

The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia

“…Interestingly, RNA-seq analysis indicated that compounds were quite selective and did not have a widespread effect on the transcriptome. This discovery opened a new perspective in targeting of RNA primary and secondary structures by chemical compounds as well as inhibiting RNA-protein interactions in human disease [199]. Prior to this, the interaction of small molecules with RNA were extensively studied in viruses.…”