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APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN

Introduction: IgA nephropathy (IgAN) is the most common disease leading to end-stage renal disease, and tubular fibrosis represents an important risk factor for disease progression. However, research on early molecular diagnostic indicators of tubular fibrosis and the mechanisms underlying disease p...

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Autores principales: Yu, Kuipeng, Ding, Lin, An, Xin, Yang, Yanjiang, Zhang, Xiaoning, Li, Luyao, Wang, Chunjie, Bai, Fang, Yang, Xiangdong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248024/
https://www.ncbi.nlm.nih.gov/pubmed/37305534
http://dx.doi.org/10.3389/fphar.2023.1181435
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author Yu, Kuipeng
Ding, Lin
An, Xin
Yang, Yanjiang
Zhang, Xiaoning
Li, Luyao
Wang, Chunjie
Bai, Fang
Yang, Xiangdong
author_facet Yu, Kuipeng
Ding, Lin
An, Xin
Yang, Yanjiang
Zhang, Xiaoning
Li, Luyao
Wang, Chunjie
Bai, Fang
Yang, Xiangdong
author_sort Yu, Kuipeng
collection PubMed
description Introduction: IgA nephropathy (IgAN) is the most common disease leading to end-stage renal disease, and tubular fibrosis represents an important risk factor for disease progression. However, research on early molecular diagnostic indicators of tubular fibrosis and the mechanisms underlying disease progression is still lacking. Methods: The GSE93798 dataset was downloaded from the GEO database. DEGs were screened and analyzed for GO and KEGG enrichment in IgAN. The least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) algorithms were applied to screen for hub secretory genes. The expression and diagnostic efficacy of hub genes were confirmed by the GSE35487 dataset. ELISA was applied to detect the expression of APOC1 in serum. The expression and localization of hub genes in IgAN were verified by the expression of IHC and IF in human kidney tissues, and the correlation of expression with clinical data was verified in the Nephroseq database. Finally, cellular experiments clarified the role of hub genes in the signaling pathway. Results: A total of 339 DEGs were identified in IgAN, of which 237 were upregulated and 102 downregulated. The KEGG signaling pathway is enriched in the ECM–receptor interaction and AGE-RAGE signaling pathway. APOC1, ALB, CCL8, CXCL2, SRPX2, and TGFBI identified six hub secretory genes using the LASSO and SVM-RFE algorithms. In vivo and in vitro experiments demonstrated that APOC1 expression was elevated in IgAN. The serum concentration of APOC1 was 1.232 ± 0.1812 μg/ml in IgAN patients, whereas it was 0.3956 ± 0.1233 μg/ml in healthy individuals. APOC1 exhibited high diagnostic efficacy for IgAN (AUC of 99.091%, specificity of 95.455%, and sensitivity of 99.141%) in the GSE93798 dataset. APOC1 expression negatively correlated with eGFR (R (2) = 0.2285, p = 0.0385) and positively correlated with serum creatinine (R (2) = 0.41, p = 0.000567) in IgAN. APOC1 exacerbated renal fibrosis, possibly in part by activating the NF-κB pathway in IgAN. Conclusion: APOC1 was identified as the core secretory gene of IgAN, which was closely associated with blood creatinine and eGFR and had significant efficacy in the diagnosis of IgAN. Mechanistic studies revealed that the knockdown of APOC1 could improve IgAN renal fibrosis by inhibiting the NF pathway, which may be a potential therapeutic target for improving renal fibrosis in IgAN.
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spelling pubmed-102480242023-06-09 APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN Yu, Kuipeng Ding, Lin An, Xin Yang, Yanjiang Zhang, Xiaoning Li, Luyao Wang, Chunjie Bai, Fang Yang, Xiangdong Front Pharmacol Pharmacology Introduction: IgA nephropathy (IgAN) is the most common disease leading to end-stage renal disease, and tubular fibrosis represents an important risk factor for disease progression. However, research on early molecular diagnostic indicators of tubular fibrosis and the mechanisms underlying disease progression is still lacking. Methods: The GSE93798 dataset was downloaded from the GEO database. DEGs were screened and analyzed for GO and KEGG enrichment in IgAN. The least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) algorithms were applied to screen for hub secretory genes. The expression and diagnostic efficacy of hub genes were confirmed by the GSE35487 dataset. ELISA was applied to detect the expression of APOC1 in serum. The expression and localization of hub genes in IgAN were verified by the expression of IHC and IF in human kidney tissues, and the correlation of expression with clinical data was verified in the Nephroseq database. Finally, cellular experiments clarified the role of hub genes in the signaling pathway. Results: A total of 339 DEGs were identified in IgAN, of which 237 were upregulated and 102 downregulated. The KEGG signaling pathway is enriched in the ECM–receptor interaction and AGE-RAGE signaling pathway. APOC1, ALB, CCL8, CXCL2, SRPX2, and TGFBI identified six hub secretory genes using the LASSO and SVM-RFE algorithms. In vivo and in vitro experiments demonstrated that APOC1 expression was elevated in IgAN. The serum concentration of APOC1 was 1.232 ± 0.1812 μg/ml in IgAN patients, whereas it was 0.3956 ± 0.1233 μg/ml in healthy individuals. APOC1 exhibited high diagnostic efficacy for IgAN (AUC of 99.091%, specificity of 95.455%, and sensitivity of 99.141%) in the GSE93798 dataset. APOC1 expression negatively correlated with eGFR (R (2) = 0.2285, p = 0.0385) and positively correlated with serum creatinine (R (2) = 0.41, p = 0.000567) in IgAN. APOC1 exacerbated renal fibrosis, possibly in part by activating the NF-κB pathway in IgAN. Conclusion: APOC1 was identified as the core secretory gene of IgAN, which was closely associated with blood creatinine and eGFR and had significant efficacy in the diagnosis of IgAN. Mechanistic studies revealed that the knockdown of APOC1 could improve IgAN renal fibrosis by inhibiting the NF pathway, which may be a potential therapeutic target for improving renal fibrosis in IgAN. Frontiers Media S.A. 2023-05-25 /pmc/articles/PMC10248024/ /pubmed/37305534 http://dx.doi.org/10.3389/fphar.2023.1181435 Text en Copyright © 2023 Yu, Ding, An, Yang, Zhang, Li, Wang, Bai and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Yu, Kuipeng
Ding, Lin
An, Xin
Yang, Yanjiang
Zhang, Xiaoning
Li, Luyao
Wang, Chunjie
Bai, Fang
Yang, Xiangdong
APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN
title APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN
title_full APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN
title_fullStr APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN
title_full_unstemmed APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN
title_short APOC1 exacerbates renal fibrosis through the activation of the NF-κB signaling pathway in IgAN
title_sort apoc1 exacerbates renal fibrosis through the activation of the nf-κb signaling pathway in igan
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248024/
https://www.ncbi.nlm.nih.gov/pubmed/37305534
http://dx.doi.org/10.3389/fphar.2023.1181435
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