Ablation of Gadd45β ameliorates the inflammation and renal fibrosis caused by unilateral ureteral obstruction

Moon, Sung-Je; Kim, Jae-Hoon; Choi, Young Keun; Lee, Chul‐Ho; Hwang, Jung Hwan

doi:10.1111/jcmm.15519

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…Dual-Specificity Phosphatase 1 (DUSP1), one of the enzymes for mitogen-activated protein kinases (MAPKs), plays a key role of initiating MAPK cascade ( Li et al, 2021 ). Growth Arrest and DNA Damage Inducible Beta (GADD45B) is also often implicated in the pathogenesis of CKD ( Moon et al, 2020 ). GADD45B serves as an anti-apoptotic factor, exerting its effects by directly binding to MKK7.…”

Section: Discussionmentioning

confidence: 99%

Development and evaluation of a chronic kidney disease risk prediction model using random forest

Mendapara

2024

Front. Genet.

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This research aims to advance the detection of Chronic Kidney Disease (CKD) through a novel gene-based predictive model, leveraging recent breakthroughs in gene sequencing. We sourced and merged gene expression profiles of CKD-affected renal tissues from the Gene Expression Omnibus (GEO) database, classifying them into two sets for training and validation in a 7:3 ratio. The training set included 141 CKD and 33 non-CKD specimens, while the validation set had 60 and 14, respectively. The disease risk prediction model was constructed using the training dataset, while the validation dataset confirmed the model’s identification capabilities. The development of our predictive model began with evaluating differentially expressed genes (DEGs) between the two groups. We isolated six genes using Lasso and random forest (RF) methods—DUSP1, GADD45B, IFI44L, IFI30, ATF3, and LYZ—which are critical in differentiating CKD from non-CKD tissues. We refined our random forest (RF) model through 10-fold cross-validation, repeated five times, to optimize the mtry parameter. The performance of our model was robust, with an average AUC of 0.979 across the folds, translating to a 91.18% accuracy. Validation tests further confirmed its efficacy, with a 94.59% accuracy and an AUC of 0.990. External validation using dataset GSE180394 yielded an AUC of 0.913, 89.83% accuracy, and a sensitivity rate of 0.889, underscoring the model’s reliability. In summary, the study identified critical genetic biomarkers and successfully developed a novel disease risk prediction model for CKD. This model can serve as a valuable tool for CKD disease risk assessment and contribute significantly to CKD identification.

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Section: Discussionmentioning

confidence: 99%

Development and evaluation of a chronic kidney disease risk prediction model using random forest

Mendapara

2024

Front. Genet.

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“…Similarly, GADD45b is a critical regulator of autoimmunity (72) that plays an important role in B cell apoptosis in response to Fas stimulation through activation of NF-kB (73). A recent report suggests that ablation of GADD45b ameliorates the inflammation and renal fibrosis caused by unilateral ureteral obstruction (UUO) in a chronic kidney disease mouse model (74). Previously it was shown that GADD45b was also induced in CD4 + T cells by inflammatory cytokines, such as IL-12 and IL-18 (75,76).…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8+ and CD4+ Regulatory T Cells in Lupus

2021

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45β and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 μg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.

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“…The colon, ileum, and liver tissues were cut at 5 μm thickness and stained separately with hematoxylin and eosin (H&E), similar to a previous study [ 23 , 24 ]. The severity of colitis was blindly assessed by a pathologist and scored using the histological scoring method [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

CrebH protects against liver injury associated with colonic inflammation via modulation of exosomal miRNA

et al. 2023

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Background Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH’s roles in the gut–liver axis remain unknown. Methods Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH−/− mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells. Results CrebH−/− mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH−/− mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH−/− mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH−/− mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD). Conclusions CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH−/− mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.

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Ablation of Gadd45β ameliorates the inflammation and renal fibrosis caused by unilateral ureteral obstruction

Cited by 9 publications

References 33 publications

Development and evaluation of a chronic kidney disease risk prediction model using random forest

Development and evaluation of a chronic kidney disease risk prediction model using random forest

Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8+ and CD4+ Regulatory T Cells in Lupus

CrebH protects against liver injury associated with colonic inflammation via modulation of exosomal miRNA

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