Macrophage transcription factor TonEBP promotes systemic lupus erythematosus and kidney injury via damage-induced signaling pathways

Yoo, Eun Jin; Oh, Kook Hwan; Piao, Honglin; Kang, Hye-Won; Jeong, Gyu Won; Park, Hyun; Lee, Chang Jun; Ryu, Hyunjin; Yang, Seung Hee; Kim, Myung Gyu; Kim, Yon Su; Park, Sung Ho; Lim, Beom Jin; Lee, Sang Min; Park, Chan Young; Choi, Soo Youn; Lee-Kwon, Whaseon; Yang, Jaeseok; Kwon, Hyug Moo

doi:10.1016/j.kint.2023.03.030

Cited by 13 publications

(13 citation statements)

References 46 publications

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“…Moreover, it was apparent that the beneficial pharmaceutical effects of PLR were mediated through several mechanisms. Previous studies have shown that mTOR and AMPK pathways are also involved in the regulation and progression of CKD ( 81 , 82 ). In the future, more in depth understanding about the remodeling ability of PLR towards the gut microbiota should be further explored and mTOR and AMPK pathways could be potential targets for subsequent research.…”

Section: Discussionmentioning

confidence: 99%

Puerariae lobatae Radix ameliorates chronic kidney disease by reshaping gut microbiota and downregulating Wnt/β‑catenin signaling

Wu,

Xue,

Zhu

et al. 2024

Mol Med Rep

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Gut microbiota dysfunction is a key factor affecting chronic kidney disease (CKD) susceptibility. Puerariae lobatae Radix (PLR), a traditional Chinese medicine and food homologous herb, is known to promote the gut microbiota homeostasis; however, its role in renoprotection remains unknown. The present study aimed to investigate the efficacy and potential mechanism of PLR to alleviate CKD. An 8-week 2% NaCl-feeding murine model was applied to induce CKD and evaluate the therapeutic effect of PLR supplementary. After gavage for 8 weeks, The medium and high doses of PLR significantly alleviated CKD-associated creatinine, urine protein increasement and nephritic histopathological injury. Moreover, PLR protected kidney from fibrosis by reducing inflammatory response and downregulating the canonical Wnt/β-catenin pathway. Furthermore, PLR rescued the gut microbiota dysbiosis and protected against high salt-induced gut barrier dysfunction. Enrichment of Akkermansia and Bifidobacterium was found after PLR intervention, the relative abundances of which were in positive correlation with normal maintenance of renal histology and function. Next, fecal microbiota transplantation experiment verified that the positive effect of PLR on CKD was, at least partially, exerted through gut microbiota reestablishment and downregulation of the Wnt/β-catenin pathway. The present study provided evidence for a new function of PLR on kidney protection and put forward a potential therapeutic strategy target for CKD.

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Section: Discussionmentioning

confidence: 99%

Puerariae lobatae Radix ameliorates chronic kidney disease by reshaping gut microbiota and downregulating Wnt/β‑catenin signaling

Wu,

Xue,

Zhu

et al. 2024

Mol Med Rep

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“…We applied ssGSEA to calculate the abundance of immune cells in LN samples and assessed the correlation between seven important m6A modulators and immune cells, and found that the majority of immune cells were significantly more infiltrated in cluster B than in cluster A, and that the m6A modulators were positively correlated with the majority of immune cells. We found that T cell, macrophage, and monocyte infiltration was higher in cluster B than in cluster A. SLE is characterized by dysregulation of autoreactive B cells and many other types of immune cells, including myeloid cells [ 20 ]. T cells are central to the pathogenesis of lupus nephritis (LN), and blockade of CD6 in a model of spontaneous lupus and immune-complex glomerulonephritis resulted in significant decreases in immune cells, inflammatory markers, and disease markers [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of m6A-regulated genes and subtype classification in lupus nephritis

Li,

Zhu

et al. 2024

BMC Nephrol

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Background Lupus nephritis (LN) is the most common and severe clinical manifestation of systemic lupus erythematosus (SLE). N6-methyladenosine (m6A) is a reversible RNA modification and has been implicated in various biological processes. However, the roles of m6A regulators in LN are not fully demonstrated. Methods We downloaded the kidney tissue transcriptome dataset of LN patients and normal controls from the GEO database and extracted the expression levels of m6A regulators. We constructed and compared Random Forest (RF) and Support Vector Machine (SVM) models, and subsequently selected featured genes to develop nomogram models. The m6A subtypes were identified based on significantly differentially expressed m6A regulators, and the m6A gene subtypes were identified based on m6A-associated differential genes, and the two m6A modification patterns were comprehensively evaluated. Results We obtained the GSE32591 and GSE112943 datasets from the GEO database, including 78 LN samples and 36 normal control samples. We extracted the expression levels of 20 m6A regulators. By RF analysis we identified 7 characteristic m6A regulators and constructed nomogramh models with these 7 genes. We identified two m6A subtypes based on these seven important m6A regulators, and the immune cell infiltration levels of the two subtype clusters were significantly different. We identified two more m6A gene subtypes based on m6A-associated DEGs. We calculated the m6A scores using the principal component analysis (PCA) algorithm and found that the m6A scores of m6A cluster A and gene cluster A were lower than those of m6A cluster B and gene cluster B. In addition, we found that the levels of inflammatory factors were also significantly different between m6A clusters and gene clusters. Conclusion This study confirms that m6A regulators are involved in the LN process through different modes of action and provide new diagnostic and therapeutic targets for LN.

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“…Mice lacking NFAT5 specifically in T cells exhibited worsened intestinal pathology in an experimental colitis model, coupled with increased interferon gamma (IFNγ) messenger RNA (mRNA) in draining lymph nodes and colon ( 55 ). In individuals with lupus nephritis (LN), it has been observed that NFAT5 expression is increased, which is positively correlated with the expression of inflammatory cytokines and the severity of proteinuria ( 56 ). Furthermore, in a mice model of pristane-induced systemic lupus erythematosus (SLE), the absence of NFAT5 in myeloid cells prevented the development of LN and SLE ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

“…In individuals with lupus nephritis (LN), it has been observed that NFAT5 expression is increased, which is positively correlated with the expression of inflammatory cytokines and the severity of proteinuria ( 56 ). Furthermore, in a mice model of pristane-induced systemic lupus erythematosus (SLE), the absence of NFAT5 in myeloid cells prevented the development of LN and SLE ( 56 ). Activation of toll-like receptors (TLRs) that respond to damage-associated molecular patterns, induced the expression of NFAT5 in macrophages via stimulation of its promoter, which was essential for the intracellular signaling downstream of TLRs.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of toll-like receptors (TLRs) that respond to damage-associated molecular patterns, induced the expression of NFAT5 in macrophages via stimulation of its promoter, which was essential for the intracellular signaling downstream of TLRs. NFAT5-deficient macrophages displayed elevated efferocytosis, and animals with myeloid deficiency of NFAT5 showed reduced Th1 and Th17 differentiation ( 56 ). However, the exact role of NFAT5 in ulcerative colitis pathogenesis requires further investigation of the complex interplay between NFAT5 and ERS-related genes.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive analysis of endoplasmic reticulum stress-associated genes signature of ulcerative colitis

et al. 2023

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BackgroundEndoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This study aims to identify pivotal molecular mechanisms related to ERS in UC pathogenesis and provide novel therapeutic targets for UC.MethodsColon tissue gene expression profiles and clinical information of UC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database, and the ERS-related gene set was downloaded from GeneCards for analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal modules and genes associated with UC. A consensus clustering algorithm was used to classify UC patients. The CIBERSORT algorithm was employed to evaluate the immune cell infiltration. Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. The external sets were used to validate and identify the relationship of ERS-related genes with biologics. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking was performed to simulate the binding conformation of small molecule compounds and key targets.ResultsThe study identified 915 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) from the colonic mucosa of UC patients and healthy controls, and these genes had good diagnostic value and were highly correlated. Five potential small-molecule drugs sharing tubulin inhibitors were identified, including albendazole, fenbendazole, flubendazole, griseofulvin, and noscapine, among which noscapine exhibited the highest correlation with a high binding affinity to the targets. Active UC and 10 ERSRGs were associated with a large number of immune cells, and ERS was also associated with colon mucosal invasion of active UC. Significant differences in gene expression patterns and immune cell infiltration abundance were observed among ERS-related subtypes.ConclusionThe results suggest that ERS plays a vital role in UC pathogenesis, and noscapine may be a promising therapeutic agent for UC by affecting ERS.

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Macrophage transcription factor TonEBP promotes systemic lupus erythematosus and kidney injury via damage-induced signaling pathways

Cited by 13 publications

References 46 publications

Puerariae lobatae Radix ameliorates chronic kidney disease by reshaping gut microbiota and downregulating Wnt/β‑catenin signaling

Puerariae lobatae Radix ameliorates chronic kidney disease by reshaping gut microbiota and downregulating Wnt/β‑catenin signaling

Analysis of m6A-regulated genes and subtype classification in lupus nephritis

Comprehensive analysis of endoplasmic reticulum stress-associated genes signature of ulcerative colitis

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