Identification of CD2, CCL5 and CCR5 as potential therapeutic target genes for renal interstitial fibrosis

Zhang, Chuanjie; Hu, Xin; Feng, Qi; Luo, Jun; Xiao, Li

doi:10.21037/atm.2019.08.62

Cited by 7 publications

(8 citation statements)

References 38 publications

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“…Thus, activation of STAT3 signaling upregulates DNMT1 expression and leads to DNA methylation (Zhang et al, 2006;Wang et al, 2017). Previous studies have demonstrated upregulation of CCL5 and STAT3 expression in kidney fibrosis, and their levels are positively associated with the degree of RIF (Bienaime et al, 2016;Pace et al, 2019;Zhang et al, 2019). Thus, CCL5/STAT3 signaling is involved in renal fibrotic diseases and is proposed to be a feasible therapeutic target for RIF.…”

Section: Discussionmentioning

confidence: 99%

“…CCL5 is a major mediator and biomarker of inflammation and it recruits monocytes, macrophages, T cells, and eosinophils to the sites of injured kidneys. Indeed, a recent study showed that the CCL5 level was significantly associated with the intensity of RIF and CCL5 was identified as a potential intervention target for RIF ( Zhang et al, 2019 ). Our data from human CKD showed that the CCL5 level was elevated significantly, while the Klotho level was significantly decreased as eGFR declined.…”

Section: Discussionmentioning

confidence: 99%

“…Whether inflammation regulates Klotho expression through DNA methylation remains to be investigated. C-C motif chemokine 5 (CCL5) is a potent proinflammatory factor that is remarkably upregulated in fibrotic kidneys ( Zhang et al, 2019 ) and exerts a pathological role during the induction and progression of RIF ( Zhang et al, 2012 ). CCL5 induces DNA methylation and influences the expression of target genes in tumors ( Wang et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Liu

et al. 2022

Front. Physiol.

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BackgroundEnhanced inflammation and reduced Klotho are common features in chronic kidney disease (CKD). Inflammation induces DNA hypermethylation. This study assessed the performance of inflammatory marker C-C motif chemokine 5 (CCL5) in epigenetic regulation of Klotho expression.MethodsFifty CKD patients and 25 matched controls were enrolled, and serum CCL5 level, sKlotho level, and DNA methylation were evaluated in these subjects. A renal interstitial fibrosis (RIF) model with CKD was induced in mice via unilateral ureteral obstruction (UUO) in vivo and human proximal tubular epithelial (HK-2) cells treated with CCL5 in vitro. 5-aza-2′-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor was given to UUO mice. Hematoxylin and eosin (HE) and Masson trichrome staining were adopted to evaluate renal pathological changes. Methylation-specific PCR was performed to assess DNA methylation of Klotho promoter in the peripheral blood leucocytes (PBLs) from CKD patients and obstructive kidney from UUO mice. CCL5, Klotho, and DNA methyltransferases (DNMTs) were determined by ELISAs, immunofluorescence, or western blotting. HK-2 cells were exposed to CCL5 with or without 5-Aza and stattic, a p-signal transducer and activator of transcription 3 (STAT3) inhibitor, and expressions of p-STAT3, DNMT1, and Klotho were determined by western blotting.ResultsCCL5 upregulation concomitant with Klotho downregulation in serum and global DNA methylation in PBLs were observed in CKD samples. UUO contributed to severe renal interstitial fibrosis and enhanced expressions of fibrotic markers. Moreover, UUO increased the CCL5 level, induced Klotho promoter methylation, suppressed Klotho level, activated p-STAT3 signaling, and upregulated DNMT1 level. A similar observation was made in HK-2 cells treated with CCL5. More importantly, 5-Aza inhibited UUO-induced Klotho hypermethylation, reversed Klotho, downregulated p-STAT3 expressions, and ameliorated RIF in vivo. The consistent findings in vitro were also obtained in HK-2 cells exposed to 5-Aza and stattic.ConclusionThe CCL5/p-STAT3/DNMT1 axis is implicated in epigenetic regulation of Klotho expression in CKD. This study provides novel therapeutic possibilities for reversal of Klotho suppression by CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Liu

et al. 2022

Front. Physiol.

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“…This approach allowed an improved understanding of the molecular mechanisms involved in cancer (21). Meanwhile, the heatmap package [version 1.0.12 (22)] was used to generate the heatmap of these DEGs.…”

Section: Methodsmentioning

confidence: 99%

Elevated mRNA expression levels of DLGAP5 are associated with poor prognosis in breast cancer

Dong

Zhang

et al. 2020

Oncol Lett

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Breast cancer is the most commonly diagnosed type of cancer and one of the leading causes of cancer-associated mortality in women. In addition, the underlying molecular mechanisms of the occurrence and development of breast cancer requires further investigation. In the present study, bioinformatics analysis was performed to identify differentially expressed genes (DEGs) between breast cancer and normal breast tissues to investigate the underlying molecular mechanisms. In addition, reverse transcription-quantitative PCR and immunohistochemistry (IHC) were performed to investigate the protein and mRNA expression levels of a specific DEG, discs large-associated protein 5 (DLGAP5). A Cell Counting Kit-8 assay and flow cytometry analysis were used to assess the effects of DLGAP5 on cell proliferation. In total, 85 DEGs were identified in the three Gene Expression Omnibus datasets, including 40 upregulated and 45 downregulated genes. In addition, 30 hub genes were identified following the construction of a protein-protein interaction network, and 28 of the 30 hub genes were established to be indicators of breast cancer prognosis. DLGAP5 was highly expressed in breast cancer specimens, and its expression levels were correlated with clinical stage and lymph node status. In addition, downregulation of DLGAP5 repressed the proliferation of breast cancer MDA-MB-231 cells and induced cell cycle arrest. Additionally, DLGAP5 was identified to be localized in the mitochondria, and the presence of a conserved microtubule-associated proteins 1A/1B light chain 3B-interacting region motif suggested that DLGAP5 may serve a role in mitophagy. The present results demonstrated an association between DLGAP5 expression levels and the clinicopathological characteristics of patients with breast cancer using IHC. In conclusion, DLGAP5 may be a promising target in the diagnosis and treatment of breast cancer.

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“…A previous study using the same GEO datasets screened CD2, CCL5, and CCR5 as potential therapeutic target genes in RIF by overlapping DEGs identified from GSE22459 and GSE76882 datasets and PPI network analysis (8). However, unlike the previous study, the candidate key genes of RIF in the present study were first identified by overlapping the RIF-related genes from WGCNA with DEGs from the two datasets.…”

Section: Discussionmentioning

confidence: 87%

Identification of key biomarkers and immune infiltration in renal interstitial fibrosis

Hu¹,

Liu²,

Zhu³

et al. 2022

Ann Transl Med

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Background: Renal interstitial fibrosis (RIF) is the common final pathway that mediates almost all progressive renal diseases. However, the underlying mechanisms of RIF have not been fully elucidated.Therefore, the current study aimed to explore the etiology of RIF and identify the key targets and immune infiltration patterns of RIF.Methods: Ribonucleic acid (RNA)-seq data of RIF and normal samples were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to screen relevant modules associated with RIF. Differentially expressed genes (DEGs) between the RIF and normal samples were identified using the limma package. Machine learning methods were used to identify hub gene signatures related to RIF. Further biochemical approaches including quantitative polymerase chain reaction (qPCR), immunoblotting and immunohistochemistry experiments were performed to verify the hub signatures in the RIF samples. Single sample gene set enrichment analysis (ssGSEA) was used to analyze the proportions of 28 immune cells in RIF and normal samples.Results: WGCNA showed 121 RIF-related genes. A total of 523 DEGs were found between the RIF and normal samples. By overlapping these genes, we obtained 78 RIF-related genes, which were mainly enriched in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with immunity and inflammation. Integrative analysis of machine learning methods showed prominin 1 (PROM1), tryptophan aspartate-containing coat protein (CORO1A), interferon-stimulated exonuclease gene 20 (ISG20), and tissue inhibitor matrix metalloproteinase 1 (TIMP1) as hub gene signatures in RIF. Further, receiver operating curve (ROC) curves implied the diagnostic role of ISG20 and CORO1A in RIF. The expression levels of ISG20 and CORO1A were significantly higher in fibrotic tubular cells and renal tissues based on biochemical approaches. The immune microenvironment was found to be markedly altered in the RIF samples, as 21 differentially infiltrated immune cells (DIICs) were found between RIF and normal samples.Conclusions: This study is the first to find that ISG20 and CORO1A are key biomarkers and to examine the landscape of immune infiltration in RIF. Our findings provide novel insights into the mechanisms and treatment of patients with RIF.

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Identification of CD2, CCL5 and CCR5 as potential therapeutic target genes for renal interstitial fibrosis

Cited by 7 publications

References 38 publications

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Elevated mRNA expression levels of DLGAP5 are associated with poor prognosis in breast cancer

Identification of key biomarkers and immune infiltration in renal interstitial fibrosis

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