RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease

Guo, Jia; Lei, M.; Cheng, Fei; Liu, Yong; Zhou, Mengwen; Wen, Zheng; Zhou, Yali; Gong, Rujun; Liu, Zhangsuo

doi:10.1038/s41419-020-2630-x

Cited by 23 publications

(29 citation statements)

References 34 publications

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“…ARE‐rich transcripts code for proteins in inflammation, cellular proliferation, RNA metabolism, and other cellular processes [52]. The ZFP36‐HuR axis is well studied in several diseases like cancer, obesity, insulin resistance, and diabetic podocytopathy [48,53,54]. Our finding, that ZFP36 is upregulated by the TNF‐α treatment (Fig.…”

Section: Discussionmentioning

confidence: 56%

Global analysis of RNA–protein interactions in TNF‐α induced alternative splicing in metabolic disorders

et al. 2021

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In this report, using the database of RNA-binding protein specificities (RBPDB) and our previously published RNA-seq data, we analyzed the interactions between RNA and RNA-binding proteins to decipher the role of alternative splicing in metabolic disorders induced by TNF-a. We identified 13 395 unique RNA-RBP interactions, including 385 unique RNA motifs and 35 RBPs, some of which (including MBNL-1 and 3, ZFP36, ZRANB2, and SNRPA) are transcriptionally regulated by TNF-a. In addition to some previously reported RBPs, such as RBMX and HuR/ELAVL1, we found a few novel RBPs, such as ZRANB2 and SNRPA, to be involved in the regulation of metabolic syndrome-associated genes that contain an enrichment of tetrameric RNA sequences (AUUU). Taken together, this study paves the way for novel RNA-protein interaction-based therapeutics for treating metabolic syndromes.

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Section: Discussionmentioning

confidence: 56%

Global analysis of RNA–protein interactions in TNF‐α induced alternative splicing in metabolic disorders

et al. 2021

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“…HuR increases in various kidney disease models and is involved in glomerulosclerosis. Another research revealed that inhibition of HuR could significantly ameliorate podocyte injury, macrophage cell infiltration as well as fibrogenic protein deposition [28]. As cytoplasmic localization of HuR is controlled by the p38/MAPK pathway, the results above support the speculation that TMAO indirectly promotes inflammation by regulating transcription factor HuR and TTP.…”

Section: Discussionmentioning

confidence: 71%

Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR

Lai¹,

Tang²,

Zhang³

et al. 2021

Kidney Blood Press Res

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Background: Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. Objectives: The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury. Method: We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to investigate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day. Results: In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue. Conclusions: Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.

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“…Similarly, we observed that IL-6 and cleaved caspased-3 expression levels were downregulated along with the reduction of HuR expression and shuttling after knockdown of HuR. Meanwhile, HuR has been reported to modulate DKD progression [ 12 ]. In our study, we found that the expression level of desmin was decreased and ZO-1 was increased when HuR knockdown.…”

Section: Discussionmentioning

confidence: 93%

“…Bioinformatics analysis found lncRNA 254693 could bind with human antigen R (HuR). HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins [ 12 ], was found to be involved in many diseases, such as hepatocellular cancer and colorectal cancer, by regulating mRNA splicing, transportation, and stability [ 13 , 14 ]. It was reported that HuR could engage with a variety of RNAs, including coding and noncoding RNA transcripts [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA ENSG00000254693 Promotes Diabetic Kidney Disease via Interacting with HuR

Lin

et al. 2022

Journal of Diabetes Research

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Diabetic kidney disease (DKD) is one of the most common complications of diabetes mellitus (DM), without suitable therapies, causing end-stage renal diseases (ESRDs) ultimately. Moreover, there is increasing evidence demonstrating that long noncoding RNAs (lncRNAs) play crucial roles in the development of DKD. Our RNA sequencing data revealed a large group of differentially expressed lncRNAs in renal tissues of DKD, of which lncRNA ENSG00000254693 (lncRNA 254693 for short) changed drastically. In this study, we found that the expression of lncRNA 254693 was increased in both DKD patients and high-glucose-induced human podocytes. 5 ′ /3 ′ RACE and Northern blot assays were used to find the full length of lncRNA ENSG00000254693 which is 558 nucleotides and nonisoform that existed in human podocyte. Downregulation of lncRNA 254693 remarkably reversed the elevation of inflammation, apoptosis, and podocyte injury caused by high glucose. Then, we did bioinformatics analysis via RBPDB and found that lncRNA 254693 can combine with HuR, a RNA binding protein. Meanwhile, immunofluorescence and in situ hybridization double staining was used to prove the existence of colocalization between them. Intriguingly, lncRNA 254693 knockdown decreased HuR levels, while HuR knockdown also decreased the level of lncRNA 254693 and its stability. After this, RNA immunoprecipitation assay results confirmed the binding association between them again. In addition, we found that HuR was increased in high glucose-induced podocytes, and the silence of HuR could alleviate podocyte injury, inflammation, and apoptosis. These results together suggested a novel feedback regulation between lncRNA 254693 and HuR which could involve in podocyte injury and may serve as a predicted target for DKD therapies.

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RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease

Cited by 23 publications

References 34 publications

Global analysis of RNA–protein interactions in TNF‐α induced alternative splicing in metabolic disorders

Global analysis of RNA–protein interactions in TNF‐α induced alternative splicing in metabolic disorders

Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR

Long Noncoding RNA ENSG00000254693 Promotes Diabetic Kidney Disease via Interacting with HuR

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