|
1
|
Guan G, Chen Y, Dong Y. Unraveling the AMPK-SIRT1-FOXO Pathway: The In-Depth Analysis and Breakthrough Prospects of Oxidative Stress-Induced Diseases. Antioxidants (Basel) 2025; 14:70. [PMID: 39857404 PMCID: PMC11763278 DOI: 10.3390/antiox14010070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025] Open
Abstract
Oxidative stress (OS) refers to the production of a substantial amount of reactive oxygen species (ROS), leading to cellular and organ damage. This imbalance between oxidant and antioxidant activity contributes to various diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative conditions. The body's antioxidant system, mediated by various signaling pathways, includes the AMPK-SIRT1-FOXO pathway. In oxidative stress conditions, AMPK, an energy sensor, activates SIRT1, which in turn stimulates the FOXO transcription factor. This cascade enhances mitochondrial function, reduces mitochondrial damage, and mitigates OS-induced cellular injury. This review provides a comprehensive analysis of the biological roles, regulatory mechanisms, and functions of the AMPK-SIRT1-FOXO pathway in diseases influenced by OS, offering new insights and methods for understanding OS pathogenesis and its therapeutic approaches.
Collapse
Affiliation(s)
| | | | - Yulan Dong
- College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China; (G.G.); (Y.C.)
| |
Collapse
|
|
2
|
Yun QS, Bao YX, Jiang JB, Guo Q. Mechanisms of norcantharidin against renal tubulointerstitial fibrosis. Pharmacol Rep 2024; 76:263-272. [PMID: 38472637 DOI: 10.1007/s43440-024-00578-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024]
Abstract
Renal tubulointerstitial fibrosis (RTIF) is a common feature and inevitable consequence of all progressive chronic kidney diseases, leading to end-stage renal failure regardless of the initial cause. Although research over the past few decades has greatly improved our understanding of the pathophysiology of RTIF, until now there has been no specific treatment available that can halt the progression of RTIF. Norcantharidin (NCTD) is a demethylated analogue of cantharidin, a natural compound isolated from 1500 species of medicinal insect, the blister beetle (Mylabris phalerata Pallas), traditionally used for medicinal purposes. Many studies have found that NCTD can attenuate RTIF and has the potential to be an anti-RTIF drug. This article reviews the recent progress of NCTD in the treatment of RTIF, with emphasis on the pharmacological mechanism of NCTD against RTIF.
Collapse
Affiliation(s)
- Qin-Su Yun
- Department of Pharmacy, The First People's Hospital of Changzhou and the 3rd Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Yu-Xin Bao
- Research Center for Medicine and Biology, Zunyi Medical University, 6 West Xuefu Road, Zunyi, 563000, Guizhou, China.
| | - Jie-Bing Jiang
- Department of Pharmacology, Naval Medical University, Shanghai, 200433, China
| | - Qian Guo
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, 881 Yonghe Road, Nantong, 226001 , Jiangsu, China.
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
| |
Collapse
|
|
3
|
Srivastava A, Tomar B, Sharma D, Rath SK. Mitochondrial dysfunction and oxidative stress: Role in chronic kidney disease. Life Sci 2023; 319:121432. [PMID: 36706833 DOI: 10.1016/j.lfs.2023.121432] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023]
Abstract
Chronic kidney disease (CKD) is associated with a variety of distinct disease processes that permanently change the function and structure of the kidney across months or years. CKD is characterized as a glomerular filtration defect or proteinuria that lasts longer than three months. In most instances, CKD leads to end-stage kidney disease (ESKD), necessitating kidney transplantation. Mitochondrial dysfunction is a typical response to damage in CKD patients. Despite the abundance of mitochondria in the kidneys, variations in mitochondrial morphological and functional characteristics have been associated with kidney inflammatory responses and injury during CKD. Despite these variations, CKD is frequently used to define some classic signs of mitochondrial dysfunction, including altered mitochondrial shape and remodeling, increased mitochondrial oxidative stress, and a marked decline in mitochondrial biogenesis and ATP generation. With a focus on the most significant developments and novel understandings of the involvement of mitochondrial remodeling in the course of CKD, this article offers a summary of the most recent advances in the sources of procured mitochondrial dysfunction in the advancement of CKD. Understanding mitochondrial biology and function is crucial for developing viable treatment options for CKD.
Collapse
Affiliation(s)
- Anjali Srivastava
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Bhawna Tomar
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Divyansh Sharma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Srikanta Kumar Rath
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
|
4
|
Hu J, Song Y, Cai X, Halina H, Qiao K, Lu J, Yin C, Gao F. A novel pyroptosis gene expression-based risk score for survival in gastric cancer. Front Endocrinol (Lausanne) 2023; 14:1120216. [PMID: 36793271 PMCID: PMC9922719 DOI: 10.3389/fendo.2023.1120216] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/09/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a highly heterogeneous disease, which makes treatment and prognosis prediction difficult. Pyroptosis plays a vital role in the development of GC and influence the prognosis of GC. Long non-coding RNAs (lncRNAs), as regulators of gene expressions, are among putative biomarkers and therapeutic targets. However, the importance of pyroptosis-associated lncRNAs is still unclear in predicting prognosis in gastric cancer. METHODS In this study, the mRNA expression profiles and clinical data of GC patients were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. A pyroptosis-related lncRNA signature was constructed based on TCGA databases by using the Least Absolute Shrinkage and Selection Operator (LASSO) method Cox regression model. GC patients from the GSE62254 database cohort were used for validation. Univariate and multivariate Cox analyses were used to determine the independent predictors for OS. Gene set enrichment analyses were performed to explore the potential regulatory pathways. The immune cell infiltration level was analyzed via CIBERSORT. RESULTS A four-pyroptosis-related lncRNA (ACVR2B-AS1, PRSS30P, ATP2B1-AS1, RMRP) signature was constructed using LASSO Cox regression analysis. GC patients were stratified into high- and low-risk groups, and patients in the high-risk group showed significant worse prognosis in TNM stage, gender, and age. The risk score was an independent predictor for OS by multivariate Cox analysis. Functional analysis indicated that the immune cell infiltrate was different between high- and low-risk groups. CONCLUSION The pyroptosis-related lncRNA prognostic signature can be used for predicting prognosis in GC. Moreover, the novel signature might provide clinical therapeutic intervention for GC patients.
Collapse
Affiliation(s)
- Jiali Hu
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center For Digestive Disease, Urumqi, China
| | - Yang Song
- Department of Gastroenterology and Hepatology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xintian Cai
- Department of Graduate School, Xinjiang Medical University, Urumqi, China
| | - Halike Halina
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center For Digestive Disease, Urumqi, China
| | - Kun Qiao
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center For Digestive Disease, Urumqi, China
| | - Jiajie Lu
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center For Digestive Disease, Urumqi, China
| | - Chengliang Yin
- Faculty of Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Feng Gao
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center For Digestive Disease, Urumqi, China
| |
Collapse
|
|
5
|
lncRNA TUG1 regulates hyperuricemia-induced renal fibrosis in a rat model. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1365-1375. [PMID: 36148952 PMCID: PMC9828301 DOI: 10.3724/abbs.2022128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Renal fibrosis is most common among chronic kidney diseases. Molecular studies have shown that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) participate in renal fibrosis, while the roles of lncRNA taurine upregulated gene 1 (TUG1) and miR-140-3p in hyperuricemia-induced renal fibrosis remain less investigated. In this study, a rat hyperuricemia model is constructed by oral administration of adenine. TUG1, miR-140-3p, and cathepsin D (CtsD) expression levels in rat models are measured. After altering TUG1, miR-140-3p, or CtsD expression in modelled rats, biochemical indices, including uric acid (UA), serum creatine (SCr), blood urea nitrogen (BUN), and 24-h urine protein are detected, pathological changes in the renal tissues, and renal fibrosis are examined. In renal tissues from hyperuricemic rats, TUG1 and CtsD are upregulated, while miR-140-3p is downregulated. Inhibiting TUG1 or CtsD or upregulating miR-140-3p relieves renal fibrosis in hyperuricemic rats. Downregulated miR-140-3p reverses the therapeutic effect of TUG1 reduction, while overexpression of CtsD abolishes the role of miR-140-3p upregulation in renal fibrosis. Collectively, this study highlights that TUG1 inhibition upregulates miR-140-3p to ameliorate renal fibrosis in hyperuricemic rats by inhibiting CtsD.
Collapse
|
|
6
|
Ghiam S, Eslahchi C, Shahpasand K, Habibi-Rezaei M, Gharaghani S. Exploring the role of non-coding RNAs as potential candidate biomarkers in the cross-talk between diabetes mellitus and Alzheimer’s disease. Front Aging Neurosci 2022; 14:955461. [PMID: 36092798 PMCID: PMC9451601 DOI: 10.3389/fnagi.2022.955461] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/04/2022] [Indexed: 11/17/2022] Open
Abstract
Background Recent research has investigated the connection between Diabetes Mellitus (DM) and Alzheimer’s Disease (AD). Insulin resistance plays a crucial role in this interaction. Studies have focused on dysregulated proteins to disrupt this connection. Non-coding RNAs (ncRNAs), on the other hand, play an important role in the development of many diseases. They encode the majority of the human genome and regulate gene expression through a variety of mechanisms. Consequently, identifying significant ncRNAs and utilizing them as biomarkers could facilitate the early detection of this cross-talk. On the other hand, computational-based methods may help to understand the possible relationships between different molecules and conduct future wet laboratory experiments. Materials and methods In this study, we retrieved Genome-Wide Association Study (GWAS, 2008) results from the United Kingdom Biobank database using the keywords “Alzheimer’s” and “Diabetes Mellitus.” After excluding low confidence variants, statistical analysis was performed, and adjusted p-values were determined. Using the Linkage Disequilibrium method, 127 significant shared Single Nucleotide Polymorphism (SNP) were chosen and the SNP-SNP interaction network was built. From this network, dense subgraphs were extracted as signatures. By mapping each signature to the reference genome, genes associated with the selected SNPs were retrieved. Then, protein-microRNA (miRNA) and miRNA-long non-coding RNA (lncRNA) bipartite networks were built and significant ncRNAs were extracted. After the validation process, by applying the scoring function, the final protein-miRNA-lncRNA tripartite network was constructed, and significant miRNAs and lncRNAs were identified. Results Hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-423-5p, and hsa-miR-3184-5p, the four most significant miRNAs, as well as NEAT1, XIST, and KCNQ1OT1, the three most important lncRNAs, and their interacting proteins in the final tripartite network, have been proposed as new candidate biomarkers in the cross-talk between DM and AD. The literature review also validates the obtained ncRNAs. In addition, miRNA/lncRNA pairs; hsa-miR-124-3p/KCNQ1OT1, hsa-miR-124-3p/NEAT1, and hsa-miR-124-3p/XIST, all expressed in the brain, and their interacting proteins in our final network are suggested for future research investigation. Conclusion This study identified 127 shared SNPs, 7 proteins, 15 miRNAs, and 11 lncRNAs involved in the cross-talk between DM and AD. Different network analysis and scoring function suggested the most significant miRNAs and lncRNAs as potential candidate biomarkers for wet laboratory experiments. Considering these candidate biomarkers may help in the early detection of DM and AD co-occurrence.
Collapse
Affiliation(s)
- Shokoofeh Ghiam
- Laboratory of Bioinformatics and Drug Design, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Changiz Eslahchi
- Department of Computer and Data Sciences, Faculty of Mathematical Sciences, Shahid-Beheshti University, Tehran, Iran
- School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
- Changiz Eslahchi,
| | - Koorosh Shahpasand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology (RI-SCBT), Tehran, Iran
| | - Mehran Habibi-Rezaei
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Sajjad Gharaghani
- Laboratory of Bioinformatics and Drug Design, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
- *Correspondence: Sajjad Gharaghani,
| |
Collapse
|
|
7
|
Lu Y, Li M, Zhou Q, Fang D, Wu R, Li Q, Chen L, Su S. Dynamic network biomarker analysis and system pharmacology methods to explore the therapeutic effects and targets of Xiaoyaosan against liver cirrhosis. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115324. [PMID: 35489663 DOI: 10.1016/j.jep.2022.115324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/26/2022] [Accepted: 04/22/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xiaoyaosan is a traditional Chinese herbal formula that has long been used to treat liver cirrhosis, liver failure, and hepatocarcinoma (HCC). However, little is known about its mechanism of action and targets in treating chronic liver disease. AIM OF THE STUDY This study aimed to detect the critical transition of HCC progression and to explore the regulatory mechanism and targets of Xiaoyaosan treating liver cirrhosis (cirrhosis) using integrative medicinal research involving system biology and pharmacology. MATERIALS AND METHODS We recruited chronic liver disease participants to obtain gene expression data and applied the dynamic network biomarker (DNB) method to identify molecular markers and the critical transition. We combined network pharmacology and DNB analysis to locate the potential DNBs (targets). Then we validated the DNBs in the liver cirrhosis rat models using Xiaoyaosan treatment. The expression of genes encoding the four DNBs, including Cebpa, Csf1, Egfr, and Il7r, were further validated in rat liver tissue using Western blot analysis. RESULTS We found EGFR, CEBPA, Csf1, Ccnb1, Rrmm2, C3, Il7r, Ccna2, and Peg10 overlap in the DNB list and Xiaoyaosan-Target-Disease (XTD) network constructed using network pharmacology databases. We investigated the diagnostic ability of each member in the DNB cluster and found EGFR, CEBPA, CSF1, and IL7R had high diagnostic abilities with AUC >0.7 and P-value < 0.05. We validated these findings in rats and found that liver function improved significantly and fibrotic changes were relieved in the Xiaoyaosan treatment group. The expression levels of CSF1 and IL7R in the Xiaoyaosan group were significantly lower than those in the cirrhosis model group. In contrast, CEBPA expression in the Xiaoyaosan group was significantly higher than that in the cirrhosis model group. The expression of EGFR in the Xiaoyaosan group was slightly decreased than in the model group but not significantly. CONCLUSION Using the DNB method and network pharmacology approach, this study revealed that CEBPA, IL7R, EGFR, and CSF1 expression was remarkably altered in chronic liver disease and thus, may play an important role in driving the progression of cirrhosis. Therefore, CEBPA, IL7R, EGFR, and CSF1 may be important targets of Xiaoyaosan in treating cirrhosis and can be considered for developing novel therapeutics.
Collapse
Affiliation(s)
- Yiyu Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Meiyi Li
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen Research Institute, Sha Tin, New Territories, Hong Kong, China
| | - Qianmei Zhou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dongdong Fang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Rong Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qingya Li
- Henan University of Chinese Medicine, Henan, 450046, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Shibing Su
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
8
|
Chen J, Zheng Y, Li L. LncRNA RPSAP52 regulates miR-423-5p/GSTM1 axis to suppress hypoxia-induced renal proximal tubular epithelial cell apoptosis. Arch Physiol Biochem 2022; 128:1066-1070. [PMID: 32299250 DOI: 10.1080/13813455.2020.1750657] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 03/25/2020] [Accepted: 03/28/2020] [Indexed: 02/05/2023]
Abstract
This study aimed to investigate the roles of RPSAP52 in renal failure. Our results showed that RPSAP52 was upregulated in plasma of renal failure patients in comparison to healthy controls. Dual luciferase reporter assay showed that RPSAP52 could interact with miR-423-5p, while overexpression of RPSAP52 and miR-423-5p did not alter the expression of each other in human renal proximal tubular epithelial cells (HRPTEpCs). In addition, overexpression of RPSAP52 increased the expression levels of GSTM1 in HRPTEpCs. Cell apoptosis assay showed that overexpression of RPSAP52 and GSTM1 decreased the apoptotic rate of HRPTEpCs under hypoxia conditions. MiR-423-5p played an opposite role and attenuated the effects of overexpressing RPSAP52 and GSTM1. Therefore, RPSAP52 may regulate miR-423-5p/GSTM1 axis to suppress hypoxia-induced HRPTEpC apoptosis.
Collapse
Affiliation(s)
- Jie Chen
- Injury Prevention Research Center, Shantou University Medical College, Shantou, P.R. China
- Department of Urology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, P.R. China
| | - Yu Zheng
- Department of Urology, The Second Affiliated Hospital of Guang Zhou Medical University, Guangzhou, China
| | - Liping Li
- Injury Prevention Research Center, Shantou University Medical College, Shantou, P.R. China
| |
Collapse
|
|
9
|
Zhang Y, Qiao X, Liu L, Han W, Liu Q, Wang Y, Xie T, Tang Y, Wang T, Meng J, Ye A, He S, Chen R, Chen C. Long noncoding RNA MAGI2-AS3 regulates the H2O2 level and cell senescence via HSPA8. Redox Biol 2022; 54:102383. [PMID: 35797800 PMCID: PMC9287730 DOI: 10.1016/j.redox.2022.102383] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/16/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Yingmin Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinhua Qiao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lihui Liu
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Wensheng Han
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qinghua Liu
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yuanyuan Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ting Xie
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yiheng Tang
- University of Chinese Academy of Sciences, Beijing, 100049, China; Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Tiepeng Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jiao Meng
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Aojun Ye
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shunmin He
- University of Chinese Academy of Sciences, Beijing, 100049, China; Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Runsheng Chen
- University of Chinese Academy of Sciences, Beijing, 100049, China; Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chang Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
10
|
Liang S, Wu YS, Li DY, Tang JX, Liu HF. Autophagy and Renal Fibrosis. Aging Dis 2022; 13:712-731. [PMID: 35656109 PMCID: PMC9116923 DOI: 10.14336/ad.2021.1027] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/27/2021] [Indexed: 12/11/2022] Open
Abstract
Renal fibrosis is a common process of almost all the chronic kidney diseases progressing to end-stage kidney disease. As a highly conserved lysosomal protein degradation pathway, autophagy is responsible for degrading protein aggregates, damaged organelles, or invading pathogens to maintain intracellular homeostasis. Growing evidence reveals that autophagy is involved in the progression of renal fibrosis, both in the tubulointerstitial compartment and in the glomeruli. Nevertheless, the specific role of autophagy in renal fibrosis has still not been fully understood. Therefore, in this review we will describe the characteristics of autophagy and summarize the recent advances in understanding the functions of autophagy in renal fibrosis. Moreover, the problem existing in this field and the possibility of autophagy as the potential therapeutic target for renal fibrosis have also been discussed.
Collapse
Affiliation(s)
- Shan Liang
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
| | - Yun-Shan Wu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
| | - Dong-Yi Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
| | - Ji-Xin Tang
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
- Shunde Women and Children's Hospital, Guangdong Medical University (Foshan Shunde Maternal and Child Healthcare Hospital), Foshan, Guangdong, China.
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
| |
Collapse
|
|
11
|
Zhang L, Gao J, Gong A, Dong Y, Hao X, Wang X, Zheng J, Ma W, Song Y, Zhang J, Xu W. The Long Noncoding RNA LINC00963 Inhibits Corneal Fibrosis Scar Formation by Targeting miR-143-3p. DNA Cell Biol 2022; 41:400-409. [PMID: 35262384 PMCID: PMC9063159 DOI: 10.1089/dna.2021.1034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Corneal fibrosis is a complication of severe corneal injury, one of the major causes of vision loss. The formation of myofibroblasts has emerged as a key stimulative factor of corneal fibrosis. In the current study, we focused on the role of LINC00963 in regulating corneal fibrosis. Transforming growth factor β1 (TGF-β1) was used to induce human corneal stromal cells differentiating into corneal myofibroblasts, and the significant increase of α-smooth muscle actin (α-SMA) was verified by quantitative real-time PCR (qRT-PCR), western blot, and immunofluorescence, respectively. LINC00963 was identified to be one-half decreased compared with nonstimulated human corneal stromal cells, indicating that it might play a role in corneal fibrosis. Interestingly, overexpression of LINC00963 resulted in decreased formation of myofibroblasts indicating that it might exhibit an inhibiting effect. Moreover, bioinformatics tool was applied to predict the downstream target of LINC00963. We investigated that LINC00963 suppressed α-SMA induced by TGF-β1 in corneal fibroblasts, at least in part, by downregulating the expression of miR-143-3p. In addition, either LINC00963 promotion or miR-143-3p inhibition could significantly decrease myofibroblast contractility and collagen I and III secretion, which are the key to contribute to corneal fibrosis. Taken together, our study identified LINC00963 as a promising therapeutic target.
Collapse
Affiliation(s)
- Lixia Zhang
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China.,Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jinning Gao
- Center for Molecular Genetics, Institute for Translational Medicine, Qingdao University, Qingdao, China
| | - Anjing Gong
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanhan Dong
- Center for Molecular Genetics, Institute for Translational Medicine, Qingdao University, Qingdao, China
| | - Xiaodan Hao
- Center for Molecular Genetics, Institute for Translational Medicine, Qingdao University, Qingdao, China
| | - Xuekang Wang
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China.,Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jian Zheng
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Wenmeng Ma
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Yiying Song
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Jie Zhang
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Wenhua Xu
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| |
Collapse
|
|
12
|
Ren Z, Wang X. Long non-coding ribonucleic acid ATP2B1-AS1 modulates endothelial permeability through regulating the miR-4729-IQGAP2 axis in diabetic retinopathy. J Diabetes Investig 2022; 13:443-452. [PMID: 34935307 PMCID: PMC8902403 DOI: 10.1111/jdi.13740] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 11/30/2022] Open
Abstract
AIMS/INTRODUCTION Mounting evidence shows that long non-coding RNAs (lncRNAs) are important to modulate the biological process of diabetic retinopathy (DR). We aimed to investigate the role of lncRNAs in DR and elucidate the exact mechanism. MATERIALS AND METHODS Real-time quantitative polymerase chain reaction was carried out to distinguish the lncRNA ATPase plasma membrane Ca2+ transporting 1 antisense RNA 1 (ATP2B1-AS1) expression in DR patients and HG-treated human retinal endothelial cells (HRECs). Dual-luciferase reporter system was used to verify that ATP2B1-AS1 could act as a microRNA (miR)-4729 sponge, and miR-4729 could bind to 3'UTR of IQ motif-containing GTPase-activating protein 2 (IQGAP2). Cell proliferation assay, wound healing migration assay, transwell assay, tube formation assay and immunofluorescence were used to investigate cell proliferation, migration and angiogenesis in HRECs. RESULTS The present results showed that ATP2B1-AS1 was downregulated in DR patients and high-glucose-induced HRECs. In gain- and loss-of-function assays, ATP2B1-AS1 overexpression could significantly reduce cell proliferation, migration, angiogenesis and permeability induced by high glucose in vitro. Additionally, we carried out dual-luciferase reporter experiments to determine that ATP2B1-AS1 could act as a miR-4729 sponge. ATP2B1-AS1 overexpression could rescue miR-4729 mimics and short hairpin RNA-IQGAP2 induced cell proliferation, migration and angiogenesis in HRECs. CONCLUSIONS The present study showed that ATP2B1-AS1 acted as a miR-4729 sponge to regulate IQGAP2 reducing high-glucose-induced endothelial dysfunction in DR.
Collapse
Affiliation(s)
- Zengjin Ren
- Department of OphthalmologyThe First Affiliated Hospital of Kangda College of Nanjing Medical University, Xuzhou Medical University Affiliated Hospital of Lianyungang, The First People's Hospital of LianyungangJiangsuChina
| | - Xue Wang
- Department of OphthalmologyThe First Affiliated Hospital of Kangda College of Nanjing Medical University, Xuzhou Medical University Affiliated Hospital of Lianyungang, The First People's Hospital of LianyungangJiangsuChina
| |
Collapse
|
|
13
|
Zhang F, Zhou X, Zou H, Liu L, Li X, Ruan Y, Xie Y, Shi M, Xiao Y, Wang Y, Zhou Y, Wu Y, Guo B. SAA1 is transcriptionally activated by STAT3 and accelerates renal interstitial fibrosis by inducing endoplasmic reticulum stress. Exp Cell Res 2021; 408:112856. [PMID: 34597680 DOI: 10.1016/j.yexcr.2021.112856] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 02/07/2023]
Abstract
Renal interstitial fibrosis (RIF) is the common irreversible pathway by which chronic kidney disease (CKD) progresses to the end stage. The transforming growth factor-β (TGF-β)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a common factor leading to inflammation-mediated RIF, but its downstream regulatory mechanism is still unclear. Bioinformatics analysis predicted that serum amyloid A protein 1 (SAA1) was one of the target genes for transcriptional activation of STAT3 signaling. As an acute phase reaction protein, SAA1 plays an important role in many inflammatory reactions, and research has suggested that SAA1 is significantly elevated in the serum of patients with CKD. In this research, multiple experiments were performed to investigate the role of SAA1 in the process of RIF. SAA1 was abnormally highly expressed in kidney tissue from individuals who underwent unilateral ureteral obstruction (UUO) and TGF-β-induced HK2 cells, and the abnormal expression was directly related to the transcriptional activation of STAT3. Additionally, SAA1 can directly target and bind valosin-containing protein (VCP)-interacting membrane selenoprotein (VIMP) to inhibit the function of the Derlin-1/VCP/VIMP complex, preventing the transportation and degradation of the misfolded protein, resulting in endoplasmic reticulum (ER) stress characterized by an increase in glucose-regulated protein 78 (GRP78) levels and ultimately promoting the occurrence and development of RIF.
Collapse
Affiliation(s)
- Fan Zhang
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Xingcheng Zhou
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Huimei Zou
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China; School of Nursing, Guizhou Medical University, Guiyang, 550025, China
| | - Lirong Liu
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550025, China; Department of Clinical Hematology, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550025, China
| | - Xiaoying Li
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China; Department of Nephrology, Guiyang First People's Hospital, Guiyang, 550025, China
| | - Yuanyuan Ruan
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Ying Xie
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Mingjun Shi
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Ying Xiao
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Yuanyuan Wang
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Yuxia Zhou
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China
| | - Yuansheng Wu
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
| | - Bing Guo
- Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China.
| |
Collapse
|
|
14
|
Wang L, Tan Y, Zhu Z, Chen J, Sun Q, Ai Z, Ai C, Xing Y, He G, Liu Y. ATP2B1-AS1 Promotes Cerebral Ischemia/Reperfusion Injury Through Regulating the miR-330-5p/TLR4-MyD88-NF-κB Signaling Pathway. Front Cell Dev Biol 2021; 9:720468. [PMID: 34712659 PMCID: PMC8545896 DOI: 10.3389/fcell.2021.720468] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 09/01/2021] [Indexed: 12/18/2022] Open
Abstract
We aim to explore the expression and function of long non-coding RNA (lncRNA) ATP2B1-AS1 in a cerebral ischemia/reperfusion (I/R) injury. In this study, we established a middle cerebral artery occlusion/reperfusion (MCAO/IR) rat model and an OGD/R PC12 cell model to evaluate the expression and role of ATP2B1-AS1 in the cerebral I/R injury. We found that the expression of ATP2B1-AS1 was upregulated in both in vitro and in vivo cerebral I/R injury models. Knockdown of ATP2B1-AS1 increased the cell viability, inhibited apoptosis, and decreased the expressions of inflammation cytokines. The target of ATP2B1-AS1 was predicted and validated to be miR-330-5p. MiR-330-5p abrogated the regulatory effect of ATP2B1-AS1 on cell viability, apoptosis, and cytokines of OGD/R PC12 cells. Furthermore, the results showed that miR-330-5p targeted TLR4, which was also upregulated in the infarcted area of MCAO/IR rats and OGD/R PC12 cells. Overexpression of ATP2B1-AS1 increased the expressions of TLR4, MyD88, and NF-κB p65 of OGD/R PC12 cells, while the effect of ATP2B1-AS1 was abrogated by miR-330-5p. In addition, knockdown of ATP2B1-AS1 decreased the latency time, increased the time of passing the platform position, reduced the cerebral infarct volume, decreased neurological deficit scores, and reduced the number of damaged neurons of MCAO/IR rats that were subjected to the Morris water maze test. Taken together, our study indicates that ATP2B1-AS1 may be an attractive therapeutic target for the treatment of cerebral ischemic injuries.
Collapse
Affiliation(s)
- Lei Wang
- Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Health Science Center, Xian Jiaotong University, Xi'an, China.,Department of Neurology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China.,Department of Neurology, Affiliated Taihe Hospital of Xian Jiaotong University Health Science Center, Shiyan, China
| | - Ying Tan
- Department of Laboratory Medicine, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Ziyu Zhu
- Department of Neurology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Jun Chen
- Department of Neurology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Qiang Sun
- Department of Neurology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Zhibin Ai
- Department of Neurology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Chunqi Ai
- Department of Mental Health Centre, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Yu Xing
- Department of Medical Image Center, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Guohou He
- Department of Neurology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Yong Liu
- Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Health Science Center, Xian Jiaotong University, Xi'an, China
| |
Collapse
|
|
15
|
Kim DH, Bang E, Ha S, Jung HJ, Choi YJ, Yu BP, Chung HY. Organ-differential Roles of Akt/FoxOs Axis as a Key Metabolic Modulator during Aging. Aging Dis 2021; 12:1713-1728. [PMID: 34631216 PMCID: PMC8460295 DOI: 10.14336/ad.2021.0225] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
FoxOs and their post-translational modification by phosphorylation, acetylation, and methylation can affect epigenetic modifications and promote the expression of downstream target genes. Therefore, they ultimately affect cellular and biological functions during aging or occurrence of age-related diseases including cancer, diabetes, and kidney diseases. As known for its key role in aging, FoxOs play various biological roles in the aging process by regulating reactive oxygen species, lipid accumulation, and inflammation. FoxOs regulated by PI3K/Akt pathway modulate the expression of various target genes encoding MnSOD, catalases, PPARγ, and IL-1β during aging, which are associated with age-related diseases. This review highlights the age-dependent differential regulatory mechanism of Akt/FoxOs axis in metabolic and non-metabolic organs. We demonstrated that age-dependent suppression of Akt increases the activity of FoxOs (Akt/FoxOs axis upregulation) in metabolic organs such as liver and muscle. This Akt/FoxOs axis could be modulated and reversed by antiaging paradigm calorie restriction (CR). In contrast, hyperinsulinemia-mediated PI3K/Akt activation inhibited FoxOs activity (Akt/FoxOs axis downregulation) leading to decrease of antioxidant genes expression in non-metabolic organs such as kidneys and lungs during aging. These phenomena are reversed by CR. The results of studies on the process of aging and CR indicate that the Akt/FoxOs axis plays a critical role in regulating metabolic homeostasis, redox stress, and inflammation in various organs during aging process. The benefical actions of CR on the Akt/FoxOs axis in metabolic and non-metabolic organs provide further insights into the molecular mechanisms of organ-differential roles of Akt/FoxOs axis during aging.
Collapse
Affiliation(s)
- Dae Hyun Kim
- 1Department of Pharmacy, College of Pharmacy, Pusan National University, Gumjung-gu, Busan 46241, Korea
| | - EunJin Bang
- 1Department of Pharmacy, College of Pharmacy, Pusan National University, Gumjung-gu, Busan 46241, Korea
| | - Sugyeong Ha
- 1Department of Pharmacy, College of Pharmacy, Pusan National University, Gumjung-gu, Busan 46241, Korea
| | - Hee Jin Jung
- 1Department of Pharmacy, College of Pharmacy, Pusan National University, Gumjung-gu, Busan 46241, Korea
| | - Yeon Ja Choi
- 2Department of Biopharmaceutical Engineering, Division of Chemistry and Biotechnology, Dongguk University, Gyeongju 38066, Korea
| | - Byung Pal Yu
- 3Department of Physiology, The University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Hae Young Chung
- 1Department of Pharmacy, College of Pharmacy, Pusan National University, Gumjung-gu, Busan 46241, Korea
| |
Collapse
|
|
16
|
Chen S, Zhou M, Ying X, Zhou C. Ellagic acid protects rats from chronic renal failure via MiR-182/FOXO3a axis. Mol Immunol 2021; 138:150-160. [PMID: 34428620 DOI: 10.1016/j.molimm.2021.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 01/20/2023]
Abstract
Studies showed that ellagic acid (EA) can significantly improve kidney function, but the renal-protective effects of EA and the potential mechanism require adequate elucidation. This study investigated the mechanisms of EA in chronic renal failure (CRF) injury. A rat model of CRF was established by 5/6 nephrectomy. The body weight, urine volume and urine protein content of the rat model of CRF with EA treatment (0/20/40 mg/kg/day) were recorded. Hematoxylin&eosin (H&E) staining, Masson staining and TUNEL were used for histopathological observation. Serum levels of creatinine value, blood urea nitrogen, superoxide dismutase, glutathione, malondialdehyde, tumor necrosis factor-α, interleukin-6 and intercellular cell adhesion molecule-1 were determined using enzyme-linked immunosorbent assay (ELISA) kits. The expressions of genes involved in CRF damage were detected by quantitative real-time PCR (qRT-PCR) and western blot. The relationships among EA, miR-182 and FOXO3a were verified by TargetScan 7.2, dual-luciferase assay and rescue experiments. In this study, EA treatment significantly increased the body weight, but reduced urination and urine protein content, renal tissue damage, collagen deposition, inflammation and the contents of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), and improved the antioxidant capacity of CRF rats. Moreover, EA treatment inhibited miR-182, TGF-β1, fibronectin and Bax levels, and promoted those of FOXO3a and Bcl-2 in CRF rats. Additionally, miR-182 specifically targeted FOXO3a, and effectively reduced the renal-protective effect of EA. Further research found that overexpressed FOXO3a partially reversed the inhibitory effect of miR-182 on CRF rats. Our results suggest that EA might reduce CRF injury in rats via miR-182/FOXO3a.
Collapse
Affiliation(s)
- Siqi Chen
- Department of Nephrology, The Affiliated People's Hospital, Ningbo University, Ningbo, Zhejiang, 315040, China
| | - Meiyang Zhou
- Department of Nephrology, The Affiliated People's Hospital, Ningbo University, Ningbo, Zhejiang, 315040, China
| | - Xuxia Ying
- Department of Intensive Care Unit, The Affiliated People's Hospital, Ningbo University, Ningbo, Zhejiang, 315040, China
| | - Canxin Zhou
- Department of Nephrology, The Affiliated People's Hospital, Ningbo University, Ningbo, Zhejiang, 315040, China.
| |
Collapse
|
|
17
|
Gu YY, Dou JY, Huang XR, Liu XS, Lan HY. Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis. Front Physiol 2021; 12:684236. [PMID: 34054586 PMCID: PMC8155637 DOI: 10.3389/fphys.2021.684236] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 12/17/2022] Open
Abstract
Renal fibrosis is one of the most characterized pathological features in chronic kidney disease (CKD). Progressive fibrosis eventually leads to renal failure, leaving dialysis or allograft transplantation the only clinical option for CKD patients. Transforming growth factor-β (TGF-β) is the key mediator in renal fibrosis and is an essential regulator for renal inflammation. Therefore, the general blockade of the pro-fibrotic TGF-β may reduce fibrosis but may risk promoting renal inflammation and other side effects due to the diverse role of TGF-β in kidney diseases. Long non-coding RNAs (lncRNAs) are RNA transcripts with more than 200 nucleotides and have been regarded as promising therapeutic targets for many diseases. This review focuses on the importance of TGF-β and lncRNAs in renal inflammation, fibrogenesis, and the potential applications of TGF-β and lncRNAs as the therapeutic targets and biomarkers in renal fibrosis and CKD are highlighted.
Collapse
Affiliation(s)
- Yue-Yu Gu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing-Yun Dou
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Nephrology, Weihai Hospital of Traditional Chinese Medicine, Weihai, China
| | - Xiao-Ru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Xu-Sheng Liu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, The Chinese University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
18
|
Wang YN, Yang CE, Zhang DD, Chen YY, Yu XY, Zhao YY, Miao H. Long non-coding RNAs: A double-edged sword in aging kidney and renal disease. Chem Biol Interact 2021; 337:109396. [PMID: 33508306 DOI: 10.1016/j.cbi.2021.109396] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/18/2020] [Accepted: 01/22/2021] [Indexed: 01/23/2023]
Abstract
Aging as one of intrinsic biological processes is a risk factor for many chronic diseases. Kidney disease is a global problem and health care burden worldwide. The diagnosis of kidney disease is currently based on serum creatinine and urea levels. Novel biomarkers may improve diagnostic accuracy, thereby allowing early prevention and treatment. Over the past few years, advances in genome analyses have identified an emerging class of noncoding RNAs that play critical roles in the regulation of gene expression and epigenetic reprogramming. Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome and could bind DNA, RNA and protein. Emerging evidence has demonstrated that lncRNAs played an important role in all stages of kidney disease. To date, only some lncRNAs were well identified and characterized, but the complexity of multilevel regulation of transcriptional programs involved in these processes remains undefined. In this review, we summarized the lncRNA expression profiling of large-scale identified lncRNAs on kidney diseases including acute kidney injury, chronic kidney disease, diabetic nephropathy and kidney transplantation. We further discussed a number of annotated lncRNAs linking with complex etiology of kidney diseases. Finally, several lncRNAs were highlighted as diagnostic biomarkers and therapeutic targets. Targeting lncRNAs may represent a precise therapeutic strategy for progressive renal fibrosis.
Collapse
Affiliation(s)
- Yan-Ni Wang
- Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China
| | - Chang-E Yang
- Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China
| | - Dan-Dan Zhang
- Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China
| | - Yuan-Yuan Chen
- Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China
| | - Xiao-Yong Yu
- Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, No. 2 Xihuamen, Xi'an, Shaanxi, 710003, China.
| | - Ying-Yong Zhao
- Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China.
| | - Hua Miao
- Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China.
| |
Collapse
|
|
19
|
Ye J, Liu J, Tang T, Xin L, Bao X, Yan Y. LINC00963 affects the development of colorectal cancer via MiR-532-3p/HMGA2 axis. Cancer Cell Int 2021; 21:87. [PMID: 33536018 PMCID: PMC7860506 DOI: 10.1186/s12935-020-01706-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Background LINC00963 is high-expressed in various carcinomas, but its expression and function in colorectal cancer (CRC) have not been explored. This study explored the role and mechanism of LINC00963 in CRC. Methods The expression of LINC00963 in CRC and its relationship with prognosis were examined by starBase and survival analysis. The effects of LINC00963, miR-532-3p and HMGA2 on the biological characteristics and EMT-related genes of CRC cells were studied by RT-qPCR, CCK-8, clone formation experiments, flow cytometry, scratch test, Transwell, and Western blot. Xenograft assay and immunohistochemistry were performed to verify the effect of LINC00963 on tumor growth. The correlation among LINC00963, miR-532-3p, and HMGA2 was analyzed by bioinformatics analysis, luciferase assay, and Pearson test. Results LINC00963 was high-expressed in CRC, and this was associated with poor prognosis of CRC. Silencing LINC00963 inhibited the activity, proliferation, migration, and invasion of CRC cells, MMP-3 and MMP-9 expressions, moreover, it also blocked cell cycle progression, and inhibited tumor growth and Ki67 expression. However, overexpression of LINC00963 showed the opposite effects to silencing LINC00963. LINC00963 targeted miR-532-3p to regulate HMGA2 expression. Down-regulation of miR-532-3p promoted cell proliferation, migration and invasion, and expressions of MMP-3 and MMP-9, and knockdown of HMGA2 reversed the effect of miR-532-3p inhibitor. Up-regulation of miR-532-3p inhibited the biological functions of CRC cells, and overexpression of HMGA2 reversed the miR-532-3p mimic effect. Conclusion LINC00963 affects the development of CRC through the miR-532-3p/HMGA2 axis.
Collapse
Affiliation(s)
- Jinjun Ye
- Department of General Surgery, Shenzhen Longgang Central Hospital, No.6082 Longgang Avenue, Longgang District, Shenzhen, 518116, Guangdong, China
| | - Jidong Liu
- Department of General Surgery, Shenzhen Longgang Central Hospital, No.6082 Longgang Avenue, Longgang District, Shenzhen, 518116, Guangdong, China
| | - Tao Tang
- Department of General Surgery, Shenzhen Longgang Central Hospital, No.6082 Longgang Avenue, Longgang District, Shenzhen, 518116, Guangdong, China
| | - Le Xin
- Department of General Surgery, Shenzhen Longgang Central Hospital, No.6082 Longgang Avenue, Longgang District, Shenzhen, 518116, Guangdong, China
| | - Xing Bao
- Department of General Surgery, Shenzhen Longgang Central Hospital, No.6082 Longgang Avenue, Longgang District, Shenzhen, 518116, Guangdong, China
| | - Yukuang Yan
- Department of General Surgery, Shenzhen Longgang Central Hospital, No.6082 Longgang Avenue, Longgang District, Shenzhen, 518116, Guangdong, China.
| |
Collapse
|
|
20
|
Iheanyichukwu W, Adegoke AO, Adebayo OG, Emmanuel U M, Egelege AP, Gona JT, Orluwene FM. Combine colorants of tartrazine and erythrosine induce kidney injury: involvement of TNF-α gene, caspase-9 and KIM-1 gene expression and kidney functions indices. Toxicol Mech Methods 2021; 31:67-72. [PMID: 32981412 DOI: 10.1080/15376516.2020.1828523] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/20/2020] [Accepted: 09/21/2020] [Indexed: 10/23/2022]
Abstract
Twenty-five male Wistar rats (140-170 g) were partitioned into 5 groups (n = 5). 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 20 mg/kg of combine Tartrazine and Erythrosine (T+E; 50:50) were administered for 23 days. Serum urea and creatinine, gene expression and profiling of pro-inflammatory cytokine (Tumor Necrosis Factor- α gene), Caspase-9 and Kidney injury molecule-1 (KIM-1) and histomorphological examination of the kidney were investigated. The fold change of relative gene expression of TNF-α gene showed significantly (p < 0.05) up-regulation in all the treated rats except for the 10 mg/kg T+E treated rats when compared to control rats. Casp-9 and KIM-1 genes were significantly (p < 0.05) up-regulated in low dose treatment (2.5 mg/kg T+E and 5 mg/kg T+E) and down-regulated in high dose treatment (10 mg/kg T+E and 20 mg/kg T+E). However, there was significant (p < 0.05) increase in serum urea concentration in the rats treated with 5 mg/kg T+E and 20 mg/kg T+E while the rats treated with 10 mg/kg T+E indicated a significant (p < 0.05) decrease. Conversely, serum creatinine concentration indicated significant (p < 0.05) increase in10mg/kg T+E and 20 mg/kg T+E treated rats versus the control. From the histomorphological examination of the kidney, there was hypertrophy of the glomeruli in relation to the size of Bowman's capsule in the 10 mg/kg T+E and 20 mg/kg T+E treated rats. Kidney function was impaired as evident in up-regulation of TNF-α gene, KIM-1 gene, and serum urea and creatinine concentration with down-regulation of Casp-9 gene. The combined treatment also tampers with the architecture of the kidney.
Collapse
Affiliation(s)
- Wopara Iheanyichukwu
- Department of Biochemistry, Faculty of Basic Medical Sciences, PAMO University of Medical Sciences, Port Harcourt, Nigeria
| | - Adebayo O Adegoke
- Department of Medical Laboratory Science, Faculty of Health Sciences, Madonna University, Okija, Nigeria
| | - Olusegun G Adebayo
- Department of Physiology, Faculty of Basic Medical Sciences, PAMO University of Medical, Port Harcourt, Nigeria
| | - Modo Emmanuel U
- Department of Biochemistry, Faculty of Sciences, Madonna University, Okija, Nigeria
| | - Aziemeola Pius Egelege
- Department of Public Health, Faculty of Health Sciences, Imo State University, Owerri, Nigeria
| | - Jeremiah T Gona
- Department of Biochemistry, Faculty of Sciences, Madonna University, Okija, Nigeria
| | - Fortune M Orluwene
- Department of Medical Laboratory Science, Faculty of Health Sciences, Madonna University, Okija, Nigeria
| |
Collapse
|
|
21
|
Guo X, Qin Y, Wang L, Dong S, Yan Y, Bian X, Zhao C. A competing endogenous RNA network reveals key lncRNAs associated with sepsis. Mol Genet Genomic Med 2021; 9:e1557. [PMID: 33237630 PMCID: PMC7963432 DOI: 10.1002/mgg3.1557] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 09/17/2020] [Accepted: 10/29/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND This study set out to determine key lncRNAs correlated with sepsis via constructing competing endogenous RNA (ceRNA) network. METHODS Three septic patients and three healthy controls were recruited to obtain lncRNA profiles in this current study. Combined with the mRNA profiles by RNA-sequencing, an integrated analysis of mRNA expression profiles downloaded from GEO was performed to obtain the differentially expressed mRNAs (DEmRNAs). Based on differentially expressed lncRNAs (DElncRNAs) and DEmRNAs acquired in this present study and differentially expressed miRNAs (DEmiRNAs) acquired in previous study, a ceRNA network was constructed. Furthermore, LINC00963 was validated in THP-1 cells by performing loss of function assays. RESULTS In this analysis, a total of 290 DEmRNAs and 46 DElncRNAs were detected in sepsis. Parkinson's disease, Oxidative phosphorylation and Cardiac muscle contraction were significantly enriched KEGG pathways in sepsis. XPO1, CUL4A, and NEDD8 were three hub proteins of sepsis-specific PPI network. A ceRNA network, which contained 16 DElncRNA-DEmiRNA pairs and 82 DEmiRNA-DEmRNA pairs, involving 5 lncRNAs, 10 miRNAs, and 60 mRNAs, was obtained. The function experiments indicated that knockdown of LINC00963 could promote cell proliferation, reduce cytokine expression, and suppress inflammasome activation and phagocytosis in LPS-induced THP-1 cells. CONCLUSION This study determined key lncRNAs involved in sepsis, which may contribute to the development for novel treatment strategy of sepsis.
Collapse
Affiliation(s)
- Xuan Guo
- Department of EmergencyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Yanjun Qin
- Department of EmergencyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Lili Wang
- Department of CardiologyHebei General HospitalShijiazhuangChina
| | - Shimin Dong
- Department of EmergencyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Yan Yan
- Department of EmergencyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Xiaohua Bian
- Department of EmergencyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Caiyan Zhao
- Department of Infectious DiseaseThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| |
Collapse
|
|
22
|
Xu X, Zhu R, Ying J, Zhao M, Wu X, Cao G, Wang K. Nephrotoxicity of Herbal Medicine and Its Prevention. Front Pharmacol 2020; 11:569551. [PMID: 33178019 PMCID: PMC7593559 DOI: 10.3389/fphar.2020.569551] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/14/2020] [Indexed: 01/31/2023] Open
Abstract
Herbal medicine (HM) has been widely used to treat diseases for thousands of years and has greatly contributed to the health of human beings. Many new drugs have been developed from HM, such as artemisinin. However, artemisinin has adverse effects, such as renal toxicity. In 1993, a study conducted in Belgium reported for the first time that the root extracts of Aristolochia obliqua S. M. Hwang led to progressive interstitial renal fibrosis. The nephrotoxicity of HM has attracted worldwide attention. More than 100 kinds of HM induce renal toxicity, including some herbs, animal HMs, and minerals. This paper aimed to summarize the HM compounds that cause nephrotoxicity, the mechanisms underlying the toxicity of these compounds, biomarkers of renal injury, and prevention strategies. These findings provide a basis for follow-up studies on the prevention and treatment of HM nephrotoxicity.
Collapse
Affiliation(s)
- Xiaofen Xu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jialiang Ying
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengting Zhao
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Xin Wu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kuilong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
23
|
Identification of candidate lncRNA biomarkers for renal fibrosis: A systematic review. Life Sci 2020; 262:118566. [PMID: 33038373 DOI: 10.1016/j.lfs.2020.118566] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/09/2020] [Accepted: 10/01/2020] [Indexed: 12/21/2022]
Abstract
AIMS To combine the results of dysregulated lncRNAs in individual renal fibrosis lncRNA expression profiling studies and to identify potential lncRNA biomarkers. MATERIALS AND METHODS We systematically searched three databases to identify lncRNA expression studies of renal fibrosis in animal models and humans. The lncRNA expression data were extracted from 24 included studies, and a lncRNA vote-counting strategy was applied to identify significant lncRNA biomarkers. The lncLocator algorithm was utilized to predict the potential subcellular localization of these lncRNAs. The predicted targets of the identified lncRNA biomarkers were obtained by searching LncBase v.2 and catRAPID. Finally, GO enrichment and KEGG pathway analyses were performed. KEY FINDINGS We recognized a significant lncRNA signature of 95 differentially expressed lncRNAs in 731 samples from rodent models of renal fibrosis and CKD patients, among which TCONS_01181049 and TCONS_01496394 were commonly upregulated in both urine and renal tissues, while lncRNA-Cancer Susceptibility Candidate 2 was downregulated in both blood and renal tissues. About 73.33% dysregulated lncRNAs in renal fibrosis animal models and 81.82% dysregulated lncRNAs in CKD patients were predicted to be localized to the cytoplasm. The most relevant biological processes and molecular functions associated with these lncRNAs were mRNA processing and RNA binding. SIGNIFICANCE The present systematic review identified 95 significantly dysregulated lncRNAs from 24 studies and future investigations should focus on exploring their potential effects on renal fibrosis and their clinical utility as biomarkers or therapeutic targets.
Collapse
|
|
24
|
Chen H, Fan Y, Jing H, Tang S, Zhou J. Emerging role of lncRNAs in renal fibrosis. Arch Biochem Biophys 2020; 692:108530. [PMID: 32768395 DOI: 10.1016/j.abb.2020.108530] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/23/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023]
Abstract
Fibrosis is the final common pathological feature of a wide variety of chronic kidney disease (CKD). However, an understanding of the mechanisms underlying the development of renal fibrosis remains challenging and controversial. As the current focus of molecular research, noncoding RNAs (ncRNAs), mainly microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular noncoding RNAs (circRNAs), have powerful and abundant biological functions, which essentially makes them mediators of the physiological and pathological processes of various system diseases. The role of ncRNAs in renal fibrosis has also received great attention in recent years, but most research has mainly focused on miRNAs. In fact, although a large number of studies of lncRNAs have emerged recently, the role these molecules play in renal fibrosis haven't been fully understood till now. Thus, this review discusses the discovery of lncRNAs and their biological functions in different types of renal fibrosis, as well as the imminent applications of these findings in clinical use. Undoubtedly, in the future, further understanding of the function of all types of lncRNAs will reveal large breakthroughs in the treatment of renal fibrosis.
Collapse
Affiliation(s)
- Hongtao Chen
- Department of Anesthesiology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, 510060, China
| | - Youling Fan
- Department of Anesthesiology, Panyu Central Hospital, Guangzhou, Guangdong Province, 511400, China
| | - Huan Jing
- Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
| | - Simin Tang
- Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
| | - Jun Zhou
- Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China.
| |
Collapse
|
|
25
|
Zhou J, Guo X, Sun Y, Ma L, Zhe R. Levels of serum Hoxb3 and sFlt-1 in pre-eclamptic patients and their effects on pregnancy outcomes. J Obstet Gynaecol Res 2020; 46:2010-2018. [PMID: 32748508 DOI: 10.1111/jog.14397] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 04/21/2020] [Accepted: 06/24/2020] [Indexed: 12/22/2022]
Abstract
AIM We aimed to explore a new approach and theoretical basis for the diagnosis, treatment and prognosis of pre-eclampsia. METHODS In total, 103 pre-eclamptic patients (study group: SG) and 100 healthy pregnant women (control group: CG) were enrolled. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of serum Hoxb3. Enzyme-linked immunosorbent assay was used to detect the content of serum sFlt-1. Pregnancy outcomes in the two groups were recorded, and the correlations of the levels of Hoxb3 and sFlt-1 with the pregnancy outcomes were analyzed. RESULTS The relative expression of serum Hoxb3 mRNA in the CG was significantly higher than that in the SG, whereas the content of serum sFlt-1 in the CG was significantly lower than that in the SG. Compared with the CG, the SG had a significantly lower number of spontaneous deliveries, higher number of cesarean deliveries and significantly higher number of uneventful perinatal births. The incidences of intrauterine growth restriction, intrauterine distress, premature infants and neonatal deaths in perinatal infants in the SG were significantly higher than those in the CG. According to the analysis of receiver operating characteristic curves, the areas under the curves of Hoxb3, sFlt-1 and their combined detection for diagnosing pre-eclampsia were 0.799, 0.856 and 0.930, respectively. The areas under the curves for predicting poor perinatal outcomes were 0.724, 0.828 and 0.871, respectively. CONCLUSION In conclusion, Hoxb3 and sFlt-1 have certain reference significance for the risk evaluation of pre-eclampsia and the adverse pregnancy outcomes of pre-eclampsia women.
Collapse
Affiliation(s)
- Jun Zhou
- Department of Obstetrics, Shenzhen People's Hospital, Shenzhen, China
| | - Xiaohui Guo
- Department of Obstetrics, Shenzhen People's Hospital, Shenzhen, China
| | - Yuan Sun
- Department of Obstetrics, Shenzhen People's Hospital, Shenzhen, China
| | - Li Ma
- Department of Obstetrics, Shenzhen People's Hospital, Shenzhen, China
| | - Ruilian Zhe
- Department of Obstetrics, Shenzhen People's Hospital, Shenzhen, China
| |
Collapse
|
|
26
|
Wang Y, Shi Y, Tao M, Zhuang S, Liu N. Peritoneal fibrosis and epigenetic modulation. Perit Dial Int 2020; 41:168-178. [PMID: 32662737 DOI: 10.1177/0896860820938239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal disease. However, peritoneal fibrosis (PF) is a common complication that ultimately leads to ultrafiltration failure and discontinuation of PD after long-term PD therapy. There is currently no effective therapy to prevent or delay this pathologic process. Recent studies have reported epigenetic modifications involved in PF, and accumulating evidence suggests that epigenetic therapies may have the potential to prevent and treat PF clinically. The major epigenetic modifications in PF include DNA methylation, histone modification, and noncoding RNAs. The mechanisms of epigenetic regulation in PF are complex, predominantly involving modification of signaling molecules, transcriptional factors, and genes. This review will describe the mechanisms of epigenetic modulation in PF and discuss the possibility of targeting them to prevent and treat this complication.
Collapse
Affiliation(s)
- Yi Wang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| | - Yingfeng Shi
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| | - Min Tao
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China.,Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China
| |
Collapse
|
|
27
|
Ghafouri-Fard S, Shoorei H, Taheri M. Non-coding RNAs are involved in the response to oxidative stress. Biomed Pharmacother 2020; 127:110228. [DOI: 10.1016/j.biopha.2020.110228] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/20/2020] [Accepted: 05/03/2020] [Indexed: 01/17/2023] Open
|
|
28
|
Jung HJ, Kim HJ, Park KK. Potential Roles of Long Noncoding RNAs as Therapeutic Targets in Renal Fibrosis. Int J Mol Sci 2020; 21:2698. [PMID: 32295041 PMCID: PMC7216020 DOI: 10.3390/ijms21082698] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/26/2020] [Accepted: 04/10/2020] [Indexed: 01/14/2023] Open
Abstract
Many studies have made clear that most of the genome is transcribed into noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), both of which can affect different cell features. LncRNAs are long heterogeneous RNAs that regulate gene expression and a variety of signaling pathways involved in cellular homeostasis and development. Several studies have demonstrated that lncRNA is an important class of regulatory molecule that can be targeted to change cellular physiology and function. The expression or dysfunction of lncRNAs is closely related to various hereditary, autoimmune, and metabolic diseases, and tumors. Specifically, recent work has shown that lncRNAs have an important role in kidney pathogenesis. The effective roles of lncRNAs have been recognized in renal ischemia, injury, inflammation, fibrosis, glomerular diseases, renal transplantation, and renal-cell carcinoma. The present review focuses on the emerging role and function of lncRNAs in the pathogenesis of kidney inflammation and fibrosis as novel essential regulators. Although lncRNAs are important players in the initiation and progression of many pathological processes, their role in renal fibrosis remains unclear. This review summarizes the current understanding of lncRNAs in the pathogenesis of kidney fibrosis and elucidates the potential role of these novel regulatory molecules as therapeutic targets for the clinical treatment of kidney inflammation and fibrosis.
Collapse
Affiliation(s)
- Hyun Jin Jung
- Department of Urology, College of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea;
| | - Hyun-Ju Kim
- Department of Pathology, College of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea;
| | - Kwan-Kyu Park
- Department of Pathology, College of Medicine, Catholic University of Daegu, Gyeongsan 42472, Korea;
| |
Collapse
|
|
29
|
Xie LB, Chen B, Liao X, Chen YF, Yang R, He SR, Pei LJ, Jiang R. LINC00963 targeting miR-128-3p promotes acute kidney injury process by activating JAK2/STAT1 pathway. J Cell Mol Med 2020; 24:5555-5564. [PMID: 32270599 PMCID: PMC7214170 DOI: 10.1111/jcmm.15211] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022] Open
Abstract
The role of long non‐coding RNAs (lncRNAs) in kidney diseases has been gradually discovered in recent years. LINC00963, as an lncRNA, was found to be involved in chronic renal failure. However, the role and molecular mechanisms of LINC00963 engaged in acute kidney injury (AKI) were still unclear. In this study, we established rat AKI models by ischaemia and reperfusion (I/R) treatment. Urea and creatinine levels were determined, and histological features of kidney tissues were examined following HE staining. CCK8 assay was chosen to assess the viability of hypoxia‐induced HK‐2 cells. Dual‐luciferase reporter gene assays were performed to verify the target relationship between LINC00963 and microRNA. The mRNA and protein levels were assayed by RT‐qPCR and Western blot, respectively. Annexin V‐FITC/PI and TUNEL staining were used to evaluate apoptosis. LINC00963 was highly expressed in the cell and rat models, and miR‐128‐3p was predicted and then verified as a target gene of LINC00963. Knockdown of LINC00963 reduced acute renal injury both in vitro and in vivo. LINC00963 activated the JAK2/STAT1 pathway to aggravate renal I/R injury. LINC00963 could target miR‐128‐3p to reduce G1 arrest and apoptosis through JAK2/STAT1 pathway to promote the progression of AKI.
Collapse
Affiliation(s)
- Li-Bo Xie
- Department of Urology, Nephropathy Clinical Medical Research Center of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Bo Chen
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xue Liao
- College of Clinical Medicine, Southwest Medical University School of Clinical Medical Sciences, Luzhou, China
| | - Yi-Feng Chen
- College of Clinical Medicine, Southwest Medical University School of Clinical Medical Sciences, Luzhou, China
| | - Rui Yang
- College of Clinical Medicine, Southwest Medical University School of Clinical Medical Sciences, Luzhou, China
| | - Si-Rong He
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Li-Jun Pei
- Department of Urology, Nephropathy Clinical Medical Research Center of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rui Jiang
- Department of Urology, Nephropathy Clinical Medical Research Center of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
|
30
|
Song KY, Zhang XZ, Li F, Ji QR. Silencing of ATP2B1-AS1 contributes to protection against myocardial infarction in mouse via blocking NFKBIA-mediated NF-κB signalling pathway. J Cell Mol Med 2020; 24:4466-4479. [PMID: 32155320 PMCID: PMC7176878 DOI: 10.1111/jcmm.15105] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 01/14/2020] [Accepted: 01/31/2020] [Indexed: 12/17/2022] Open
Abstract
Myocardial infarction (MI) is an acute coronary syndrome that refers to tissue infarction of the myocardium. This study aimed to investigate the effect of long intergenic non‐protein‐coding RNA (lincRNA) ATPase plasma membrane Ca2+ transporting 1 antisense RNA 1 (ATP2B1‐AS1) against MI by targeting nuclear factor‐kappa‐B inhibitor alpha (NFKBIA) and mediating the nuclear factor‐kappa‐B (NF‐κB) signalling pathway. An MI mouse model was established and idenepsied by cardiac function evaluation. It was determined that ATP2B1‐AS1 was highly expressed, while NFKBIA was poorly expressed and NF‐κB signalling pathway was activated in MI mice. Cardiomyocytes were extracted from mice and introduced with a series of mouse ATP2B1‐AS1 vector, NFKBIA vector, siRNA‐mouse ATP2B1‐AS1 and siRNA‐NFKBIA. The expression of NF‐κBp50, NF‐κBp65 and IKKβ was determined to idenepsy whether ATP2B1‐AS1 and NFKBIA affect the NF‐κB signalling pathway, the results of which suggested that ATP2B1‐AS1 down‐regulated the expression of NFKBIA and activated the NF‐κB signalling pathway in MI mice. Based on the data from assessment of cell viability, cell cycle, apoptosis and levels of inflammatory cytokines, either silencing of mouse ATP2B1‐AS1 or overexpression of NFKBIA was suggested to result in reduced cardiomyocyte apoptosis and expression of inflammatory cytokines, as well as enhanced cardiomyocyte viability. Our study provided evidence that mouse ATP2B1‐AS1 silencing may have the potency to protect against MI in mice through inhibiting cardiomyocyte apoptosis and inflammation, highlighting a great promise as a novel therapeutic target for MI.
Collapse
Affiliation(s)
- Kai-You Song
- Department of Cardiology, Linyi People's Hospital, Linyi, China
| | - Xian-Zhao Zhang
- Department of Cardiology, Linyi People's Hospital, Linyi, China
| | - Feng Li
- Clinical Laboratory, The Third People's Hospital of Linyi, Linyi, China
| | - Qing-Rong Ji
- Department of Cardiology, Linyi People's Hospital, Linyi, China
| |
Collapse
|
|
31
|
MALAT1: a therapeutic candidate for a broad spectrum of vascular and cardiorenal complications. Hypertens Res 2019; 43:372-379. [PMID: 31853043 DOI: 10.1038/s41440-019-0378-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/15/2019] [Accepted: 11/15/2019] [Indexed: 01/26/2023]
Abstract
Cardiovascular and renal complications cover a wide array of diseases. The most commonly known overlapping complications include cardiac and renal fibrosis, cardiomyopathy, cardiac hypertrophy, hypertension, and cardiorenal failure. The known or reported causes for the abovementioned complications include injury, ischemia, infection, and metabolic stress. To date, various targets have been reported and investigated in detail that are considered to be the cause of these complications. In the past 5 years, the role of noncoding RNAs has emerged in the area of cardiovascular and renal research, especially in relation to metabolic stress. The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) has shown immense promise among the long noncoding RNA targets for treating cardiorenal complications. In this review, we shed light on the role of MALAT1 as a primary and novel target in treating cardiovascular and renal diseases as a whole.
Collapse
|
|
32
|
Nagarajah S, Xia S, Rasmussen M, Tepel M. Endogenous intronic antisense long non-coding RNA, MGAT3-AS1, and kidney transplantation. Sci Rep 2019; 9:14743. [PMID: 31611608 PMCID: PMC6791892 DOI: 10.1038/s41598-019-51409-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 09/28/2019] [Indexed: 11/09/2022] Open
Abstract
β-1,4-mannosylglycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3) is a key molecule for the innate immune system. We tested the hypothesis that intronic antisense long non-coding RNA, MGAT3-AS1, can predict delayed allograft function after kidney transplantation. We prospectively assessed kidney function and MGAT3-AS1 in 129 incident deceased donor kidney transplant recipients before and after transplantation. MGAT3-AS1 levels were measured in mononuclear cells using qRT-PCR. Delayed graft function was defined by at least one dialysis session within 7 days of transplantation. Delayed graft function occurred in 22 out of 129 transplant recipients (17%). Median MGAT3-AS1 after transplantation was significantly lower in patients with delayed graft function compared to patients with immediate graft function (6.5 × 10−6, IQR 3.0 × 10−6 to 8.4 × 10−6; vs. 8.3 × 10−6, IQR 5.0 × 10−6 to 12.8 × 10−6; p < 0.05). The median preoperative MGAT3-AS1 was significantly lower in kidney recipients with delayed graft function (5.1 × 10−6, IQR, 2.4 × 10−6 to 6.8 × 10−6) compared to recipients with immediate graft function (8.9 × 10−6, IQR, 6.8 × 10−6 to 13.4 × 10−6; p < 0.05). Receiver-operator characteristics showed that preoperative MGAT3-AS1 predicted delayed graft function (area under curve, 0.83; 95% CI, 0.65 to 1.00; p < 0.01). We observed a positive predictive value of 0.57, and a negative predictive value of 0.95. Long non-coding RNA, MGAT3-AS1, indicates short-term outcome in patients with deceased donor kidney transplantation.
Collapse
Affiliation(s)
- Subagini Nagarajah
- Odense University Hospital, Department of Nephrology, Odense, Denmark.,University of Southern Denmark, Institute of Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research, Odense, Denmark
| | - Shengqiang Xia
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
| | | | - Martin Tepel
- Odense University Hospital, Department of Nephrology, Odense, Denmark. .,University of Southern Denmark, Institute of Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research, Odense, Denmark.
| |
Collapse
|
|
33
|
Garg M, Maurya N. WNT/β-catenin signaling in urothelial carcinoma of bladder. World J Nephrol 2019; 8:83-94. [PMID: 31624709 PMCID: PMC6794554 DOI: 10.5527/wjn.v8.i5.83] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 08/14/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Urothelial carcinoma of bladder is the second most prevalent genitourinary disease. It is a highly heterogeneous disease as it represents a spectrum of neoplasms, including non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and metastatic lesions. Genome-wide approaches and candidate gene analysis suggest that malignant transformation of the bladder is multifactorial and a multitude of genes are involved in the development of MIBC or NMIBC phenotypes. Wnt signaling is being examined to control and maintain balance between stemness and differentiation in adult stem cell niches. Owing to its participation in urothelial development and maintenance of adult urothelial tissue homeostasis, the components of Wnt signaling are reported as an important diagnostic and prognostic markers as well as novel therapeutic targets. Mutations/epigenetic alterations in the key molecules of Wnt/β-catenin canonical pathway have been linked with tumorigenesis, development of drug resistance and enhanced survival. Present review extends our understanding on the functions of key regulatory molecules of canonical Wnt/β-catenin pathway in urothelial tumorigenesis by inducing cancer stem cell phenotype (UCSCs). UCSCs may be responsible for tumor heterogeneity, high recurrence rates and complex biological behavior of bladder cancer. Therefore, understanding the role of UCSCs and the regulatory mechanisms that are responsible for high relapse rates and metastasis could help to develop pathway inhibitors and augment current therapies. Potential implications in the treatment of urothelial carcinoma of bladder by targeting this pathway primarily in UCSCs as well as in bulk tumor population that are responsible for high relapse rates and metastasis may facilitate potential therapeutic avenues and better prognosis.
Collapse
Affiliation(s)
- Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
| | - Niharika Maurya
- Department of Biochemistry, University of Lucknow, Lucknow 226007, India
| |
Collapse
|
|
34
|
Cheng Z. The FoxO-Autophagy Axis in Health and Disease. Trends Endocrinol Metab 2019; 30:658-671. [PMID: 31443842 DOI: 10.1016/j.tem.2019.07.009] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 07/02/2019] [Accepted: 07/08/2019] [Indexed: 12/21/2022]
Abstract
Autophagy controls cellular remodeling and quality control. Dysregulated autophagy has been implicated in several human diseases including obesity, diabetes, cardiovascular disease, neurodegenerative diseases, and cancer. Current evidence has revealed that FoxO (forkhead box class O) transcription factors have a multifaceted role in autophagy regulation and dysregulation. Nuclear FoxOs transactivate genes that control the formation of autophagosomes and their fusion with lysosomes. Independently of transactivation, cytosolic FoxO proteins induce autophagy by directly interacting with autophagy proteins. Autophagy is also controlled by FoxOs through epigenetic mechanisms. Moreover, FoxO proteins can be degraded directly or indirectly by autophagy. Cutting-edge evidence is reviewed that the FoxO-autophagy axis plays a crucial role in health and disease.
Collapse
Affiliation(s)
- Zhiyong Cheng
- Food Science and Human Nutrition Department, The University of Florida, Gainesville, FL 32611, USA.
| |
Collapse
|
|
35
|
Zhang L, Wang H. Long Non-coding RNA in CNS Injuries: A New Target for Therapeutic Intervention. MOLECULAR THERAPY-NUCLEIC ACIDS 2019; 17:754-766. [PMID: 31437654 PMCID: PMC6709344 DOI: 10.1016/j.omtn.2019.07.013] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 07/17/2019] [Accepted: 07/17/2019] [Indexed: 12/15/2022]
Abstract
CNS injuries, such as traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and cerebral ischemic stroke, are important causes of death and long-term disability worldwide. As an important class of pervasive genes involved in many pathophysiological processes, long non-coding RNAs (lncRNAs) have received attention in the past decades. Multiple studies indicate that lncRNAs are abundant in the CNS and have a key role in brain function as well as many neurological disorders, especially in CNS injuries. Several investigations have deciphered that regulation of lncRNAs exert pro-angiogenesis, anti-apoptosis, and anti-inflammation effects in CNS injury via different molecules and pathways, including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch, and p53. Thus, lncRNAs show great promise as molecular targets in CNS injuries. In this article, we provide an updated review of the current state of our knowledge about the relationship between lncRNAs and CNS injuries, highlighting the specific roles of lncRNAs in CNS injuries.
Collapse
Affiliation(s)
- Li Zhang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - Handong Wang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
| |
Collapse
|
|
36
|
Expression Profiles of Long Noncoding RNA and mRNA in Epicardial Adipose Tissue in Patients with Heart Failure. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3945475. [PMID: 31355260 PMCID: PMC6637716 DOI: 10.1155/2019/3945475] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 06/27/2019] [Indexed: 01/23/2023]
Abstract
The expression profile of long noncoding RNA (lncRNA) in human epicardial adipose tissue (EAT) has not been widely studied. In the present study, we performed RNA sequencing to analyze the expression profiles of lncRNA and mRNA in EAT in coronary artery disease (CAD) patients with and without heart failure (HF). Our results showed RNA sequencing disclosed 35673 mRNA and 11087 lncRNA corresponding to 15554 genes in EAT in total, while 30 differentially expressed lncRNAs (17 upregulated and 13 downregulated) and 278 differentially expressed mRNAs (129 upregulated and 149 downregulated) were discriminated between CAD patients with and without HF (P<0.05; fold change>2); lncRNA ENST00000610659 drew specific attention for it was the top upregulated lncRNA with highest fold change and corresponded to UNC93B1 gene, which was proved to be related to HF and encoded UNC93B1 protein regulating toll-like receptor signaling, and both of them significantly increased in HF patients in qRT-PCR validation; the top significant upregulated enriched GO terms and KEGG pathway analysis were regulation of lymphocyte activation (GO:0051249) and T cell receptor signaling pathway (hsa04660), respectively. The current findings support the fact that EAT lncRNAs are involved in the inflammatory response leading to the development of HF.
Collapse
|
|
37
|
Long Non-Coding RNAs in Kidney Disease. Int J Mol Sci 2019; 20:ijms20133276. [PMID: 31277300 PMCID: PMC6650856 DOI: 10.3390/ijms20133276] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/30/2019] [Accepted: 07/01/2019] [Indexed: 02/01/2023] Open
Abstract
Non-coding RNA species contribute more than 90% of all transcripts and have gained increasing attention in the last decade. One of the most recent members of this group are long non-coding RNAs (lncRNAs) which are characterized by a length of more than 200 nucleotides and a lack of coding potential. However, in contrast to this simple definition, lncRNAs are heterogenous regarding their molecular function—including the modulation of small RNA and protein function, guidance of epigenetic modifications and a role as enhancer RNAs. Furthermore, they show a highly tissue-specific expression pattern. These aspects already point towards an important role in cellular biology and imply lncRNAs as players in development, health and disease. This view has been confirmed by numerous publications from different fields in the last years and has raised the question as to whether lncRNAs may be future therapeutic targets in human disease. Here, we provide a concise overview of the current knowledge on lncRNAs in both glomerular and tubulointerstitial kidney disease.
Collapse
|
|
38
|
Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis. Int J Mol Sci 2019; 20:ijms20081977. [PMID: 31018516 PMCID: PMC6515288 DOI: 10.3390/ijms20081977] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/19/2019] [Accepted: 04/20/2019] [Indexed: 12/15/2022] Open
Abstract
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions.
Collapse
|
|
39
|
Liu Z, Wang Y, Shu S, Cai J, Tang C, Dong Z. Non-coding RNAs in kidney injury and repair. Am J Physiol Cell Physiol 2019; 317:C177-C188. [PMID: 30969781 DOI: 10.1152/ajpcell.00048.2019] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Acute kidney injury (AKI) is a major kidney disease featured by a rapid decline of renal function. Pathologically, AKI is characterized by tubular epithelial cell injury and death. Besides its acute consequence, AKI contributes critically to the development and progression of chronic kidney disease (CKD). After AKI, surviving tubular cells regenerate to repair. Normal repair restores tubular integrity, while maladaptive or incomplete repair results in renal fibrosis and eventually CKD. Non-coding RNAs (ncRNAs) are functional RNA molecules that are transcribed from DNA but not translated into proteins, which mainly include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs), and tRNAs. Accumulating evidence suggests that ncRNAs play important roles in kidney injury and repair. In this review, we summarize the recent advances in the understanding of the roles of ncRNAs, especially miRNAs and lncRNAs in kidney injury and repair, discuss the potential application of ncRNAs as biomarkers of AKI as well as therapeutic targets for treating AKI and impeding AKI-CKD transition, and highlight the future research directions of ncRNAs in kidney injury and repair.
Collapse
Affiliation(s)
- Zhiwen Liu
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Ying Wang
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Shaoqun Shu
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Juan Cai
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Chengyuan Tang
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Zheng Dong
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia
| |
Collapse
|
|
40
|
Bijkerk R, Au YW, Stam W, Duijs JMGJ, Koudijs A, Lievers E, Rabelink TJ, van Zonneveld AJ. Long Non-coding RNAs Rian and Miat Mediate Myofibroblast Formation in Kidney Fibrosis. Front Pharmacol 2019; 10:215. [PMID: 30914951 PMCID: PMC6421975 DOI: 10.3389/fphar.2019.00215] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/20/2019] [Indexed: 12/19/2022] Open
Abstract
There is an increasing prevalence of chronic kidney disease (CKD), which associates with the development of interstitial fibrosis. Pericytes (perivascular fibroblasts) provide a major source of α-SMA-positive myofibroblasts that are responsible for the excessive deposition of extracellular matrix. In order to identify pericyte long non-coding RNAs (lncRNAs) that could serve as a target to decrease myofibroblast formation and counteract the progression of kidney fibrosis we employed two models of experimental kidney injury, one focused on kidney fibrosis (unilateral ureteral obstruction; UUO), and one focused on acute kidney injury that yields kidney fibrosis in the longer term (unilateral ischemia-reperfusion injury; IRI). This was performed in FoxD1-GC;tdTomato stromal cell reporter mice that allowed pericyte fate tracing. Tomato red-positive FoxD1-derivative cells of control and injured kidneys were FACS-sorted and used for lncRNA and mRNA profiling yielding a distinctive transcriptional signature of pericytes and myofibroblasts with 244 and 586 differentially expressed lncRNAs (>twofold, P < 0.05), in the UUO and IRI models, respectively. Next, we selected two differentially expressed and conserved lncRNAs, Rian (RNA imprinted and accumulated in nucleus) and Miat (Myocardial infarction associated transcript), and explored their potential regulatory role in myofibroblast formation through knockdown of their function with gapmers. While Miat was upregulated in myofibroblasts of UUO and IRI in mice, gapmer silencing of Miat attenuated myofibroblast formation as evidenced by decreased expression of α-SMA, col1α1, SMAD2, and SMAD3, as well as decreased α-SMA and pro-collagen-1α1 protein levels. In contrast, silencing Rian, which was found to be downregulated in kidney myofibroblast after IRI and UUO, resulted in increased myofibroblast formation. In addition, we found microRNAs that were previously linked to Miat (miR-150) and Rian (14q32 miRNA cluster), to be dysregulated in the FoxD1-derivative cells, suggesting a possible interaction between miRNAs and these lncRNAs in myofibroblast formation. Taken together, lncRNAs play a regulatory role in myofibroblast formation, possibly through interacting with miRNA regulation, implicating that understanding their biology and their modulation may have the potential to counteract the development of renal fibrosis.
Collapse
Affiliation(s)
- Roel Bijkerk
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Yu Wah Au
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Wendy Stam
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Jacques M G J Duijs
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Angela Koudijs
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Ellen Lievers
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Ton J Rabelink
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands
| |
Collapse
|
|
41
|
RNA Binding Protein HuR Promotes Autophagosome Formation by Regulating Expression of Autophagy-Related Proteins 5, 12, and 16 in Human Hepatocellular Carcinoma Cells. Mol Cell Biol 2019; 39:MCB.00508-18. [PMID: 30602494 PMCID: PMC6399664 DOI: 10.1128/mcb.00508-18] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 12/18/2018] [Indexed: 12/16/2022] Open
Abstract
Autophagy is a process of lysosomal self-degradation of cellular components by forming autophagosomes. Autophagosome formation is an essential process in autophagy and is fine-tuned by various autophagy-related gene (ATG) products, including ATG5, ATG12, and ATG16. Although several reports have shown that numerous factors affect multiple levels of gene regulation to orchestrate cellular autophagy, the detailed mechanism of autophagosome formation still needs further investigation. In this study, we demonstrate that the RNA binding protein HuR (human antigen R) performs an essential function in autophagosome formation. We observe that HuR silencing leads to inhibition of autophagosome formation and autophagic flux in liver cells. Ribonucleoprotein immunoprecipitation (RIP) assay allows the identification of ATG5, ATG12, and ATG16 mRNAs as the direct targets of HuR. We further show that HuR mediates the translation of ATG5, ATG12, and ATG16 mRNAs by binding to their 3' untranslated regions (UTRs). In addition, we show that HuR expression positively correlates with the levels of ATG5 and ATG12 in hepatocellular carcinoma (HCC) cells. Collectively, our results suggest that HuR functions as a pivotal regulator of autophagosome formation by enhancing the translation of ATG5, ATG12, and ATG16 mRNAs and that augmented expression of HuR and ATGs may participate in the malfunction of autophagy in HCC cells.
Collapse
|
|
42
|
Long Noncoding RNAs in the Regulation of Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1318795. [PMID: 30911342 PMCID: PMC6398004 DOI: 10.1155/2019/1318795] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 11/29/2018] [Accepted: 12/18/2018] [Indexed: 12/25/2022]
Abstract
Oxidative stress takes responsibility for various diseases, such as chronic obstructive pulmonary disease (COPD), Alzheimer's disease (AD), and cardiovascular disease; nevertheless, there is still a lack of specific biomarkers for the guidance of diagnosis and treatment of oxidative stress-related diseases. In recent years, growing studies have documented that oxidative stress has crucial correlations with long noncoding RNAs (lncRNAs), which have been identified as important transcriptions involving the process of oxidative stress, inflammation, etc. and been regarded as the potential specific biomarkers. In this paper, we review links between oxidative stress and lncRNAs, highlight lncRNAs that refer to oxidative stress, and conclude that lncRNAs have played a negative or positive role in the oxidation/antioxidant system, which may be helpful for the further investigation of specific biomarkers of oxidative stress-related diseases.
Collapse
|
|
43
|
Zhou H, Qiu ZZ, Yu ZH, Gao L, He JM, Zhang ZW, Zheng J. Paeonol reverses promoting effect of the HOTAIR/miR-124/Notch1 axis on renal interstitial fibrosis in a rat model. J Cell Physiol 2019; 234:14351-14363. [PMID: 30714138 DOI: 10.1002/jcp.28137] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 12/18/2018] [Indexed: 01/17/2023]
Abstract
Renal interstitial fibrosis (RIF) is a common manifestation of inflammatory and noninflammatory renal diseases, which correlates to renal excretory dysfunction. Recently, the long noncoding RNAs (lncRNAs) have been demonstrated to be involved in the development of various renal diseases. Here, we aim to determine whether paeonol (PAE) affects RIF with involvement of the lncRNA HOX transcript antisense intergenic RNA (HOTAIR)/microRNA-124 (miR-124)/Notch1 axis. RIF rat models were established by performing unilateral ureteral occlusion (UUO), in which interactions between HOTAIR, Notch1, and miR-124 were determined. To identify the roles of PAE and HOTAIR in RIF, rats were injected with HOTAIR or PAE. Subsequently, to further investigate the underlying mechanism of PAE in RIF, epithelial to mesenchymal transition (EMT)- and migration-related genes in NRK-49F cells were measured. Next, rats were further treated with IMR-1 (inhibitor of the Notch1/Jagged1 signaling pathway) to determine how PAE influences the Notch1/Jagged1 signaling pathway. HOTAIR interacted with miR-124, and miR-124 directly targeted Notch1, and HOTAIR was observed to be upregulated in RIF rats. PAE was found to decrease HOTAIR and Notch1 expression but to increase the miR-124 expression in RIF rats. PAE inhibited EMT and migration of NRK-49F cells facilitated by HOTAIR. HOTAIR activated the Notch1/Jagged1 signaling pathway by downregulating miR-124, while PAE reversed these effects of HOTAIR on the Notch1/Jagged1 signaling pathway. Overall, our study demonstrates the contributory effect of lncRNA HOTAIR on RIF by activating the Notch1/Jagged1 signaling pathway via inhibition of miR-124, whereas administration of PAE can alleviate the effects of HOTAIR on RIF.
Collapse
Affiliation(s)
- Hao Zhou
- Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (The People's Hospital of Fujian Province), Fuzhou, People's Republic of China
| | - Zhen-Zhen Qiu
- Department of Physical Education, Minjiang University, Fuzhou, People's Republic of China
| | - Zuo-Hua Yu
- Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (The People's Hospital of Fujian Province), Fuzhou, People's Republic of China
| | - Lin Gao
- Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (The People's Hospital of Fujian Province), Fuzhou, People's Republic of China
| | - Ji-Ming He
- Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (The People's Hospital of Fujian Province), Fuzhou, People's Republic of China
| | - Zhi-Wei Zhang
- Department of Research, Beijing Zhong Jian Dong Ke Company, Beijing, People's Republic of China
| | - Jian Zheng
- Department of Pediatrics, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (The People's Hospital of Fujian Province), Fuzhou, People's Republic of China
| |
Collapse
|
|
44
|
Wang M, Wu W, Li L, He J, Huang S, Chen S, Chen J, Long M, Yang S, Li P. Analysis of the miRNA Expression Profiles in the Zearalenone-Exposed TM3 Leydig Cell Line. Int J Mol Sci 2019; 20:E635. [PMID: 30717214 PMCID: PMC6386897 DOI: 10.3390/ijms20030635] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/13/2019] [Accepted: 01/30/2019] [Indexed: 12/13/2022] Open
Abstract
Zearalenone (ZEN), an important environmental pollutant, can cause serious harm to human and animal health. The aim of our study was to examine the effect of zearalenone (ZEN) on miRNA expression profiles in the mouse Leydig cell line (TM3 Leydig cell line) by miRNA sequencing. The effect of ZEN on the viability of TM3 Leydig cells was verified by Cell Counting Kit-8 (CCK-8). MiRNA sequencing was performed 24 h after the exposure of TM3 Leydig cells with 50 μmol/L of ZEN. Bioinformatics predicted the miRNA target genes, performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and conducted miRNA-gene-pathway mapping to show the relationship between miRNA, the target gene, and the signalling pathway. The expression levels of miRNA and the miRNA target genes associated with ZEN toxicology were verified by quantitative real-time polymerase chain reaction. The miRNA sequencing revealed a significant change (p < 0.05) in the 197 miRNAs in the ZEN-treated and control groups, among which 86 were up-regulated and 111 were down-regulated. GO analysis of the target genes of these miRNAs indicated various biological functions. KEGG analysis showed that the predicted miRNA target genes were involved in signalling pathways, such as cancer, apoptosis, and oxidation, namely, the Ras signalling pathway, Rap1 signalling pathway, PI3K-AKT signalling pathway, Foxo signalling pathway, and AMPK signalling pathway. These results suggest that ZEN, as an estrogen-like toxin, is regulated by microRNAs. Our results can help to examine the toxicological effects of ZEN-regulated miRNAs on germ cells.
Collapse
Affiliation(s)
- Mingyang Wang
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Weiwei Wu
- Institute of Animal Science, Xinjiang Academy of Animal Sciences, Urumqi 830000, China.
| | - Lin Li
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
- Fushun modern agriculture and poverty alleviation and development promotion center, Fushun 113006, China.
| | - Jianbin He
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Sheng Huang
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Si Chen
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Jia Chen
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Miao Long
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Shuhua Yang
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| | - Peng Li
- Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China.
| |
Collapse
|