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Sun L, Huang Z, Fei S, Ni B, Wang Z, Chen H, Tao J, Han Z, Ju X, Gu M, Tan R. Vascular calcification progression and its association with mineral and bone disorder in kidney transplant recipients. Ren Fail 2023; 45:2276382. [PMID: 37936391 PMCID: PMC10653689 DOI: 10.1080/0886022x.2023.2276382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND The assessment and prevention of vascular calcification (VC) in kidney transplant recipients (KTRs) have not been systematically studied. We aimed to evaluate VC change one year after kidney transplantation (KT) and identify their influencing factors. METHODS 95 KTRs (68 males; ages 40.2 ± 10.8 years) were followed one year after KT. Changes in bone mineral density (BMD) and bone metabolism biomarkers were assessed. Coronary artery calcification (CAC) and thoracic aortic calcification (TAC) were measured using 192-slice third-generation dual-source CT. The relationship between bone metabolism indicators and VC and the factors influencing VC were analyzed. RESULTS Postoperative estimated glomerular filtration rate was 79.96 ± 24.18 mL/min*1.73 m2. One year after KT, serum phosphorus, intact parathyroid hormone (iPTH), osteocalcin, type I collagen N-terminal peptide (NTx), type I collagen C-terminal peptide, and BMD decreased, 25-hydroxyvitamin D remained low, and VC increased. Post-CAC and TAC were negatively correlated with pre-femoral neck BMD, and TAC was positively correlated with post-calcium. CAC and TAC change were positively correlated with post-calcium and 25-hydroxyvitamin D. Increased CAC was positively associated with hemodialysis and pre-femoral neck osteopenia. CAC change was positively associated with prediabetes, post-calcium, and pre-CAC and negatively associated with preoperative and postoperative femoral neck BMD, and NTx change. Increased TAC was positively associated with age, prediabetes, preoperative parathyroid hyperplasia/nodule, post-calcium, and post-femoral neck osteopenia. TAC change was positively associated with age, diabetes, pre-triglyceride, pre-TAC, dialysis time, post-calcium and post-iPTH, and negatively associated with post-femoral neck BMD. CONCLUSIONS Mineral and bone disorders persisted, and VC progressed after KT, showing a close relationship.
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Affiliation(s)
- Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhengkai Huang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Fei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bin Ni
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaobing Ju
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Gu
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Rai R, Sun T, Ramirez V, Lux E, Eren M, Vaughan DE, Ghosh AK. Acetyltransferase p300 inhibitor reverses hypertension-induced cardiac fibrosis. J Cell Mol Med 2019; 23:3026-3031. [PMID: 30710427 PMCID: PMC6433695 DOI: 10.1111/jcmm.14162] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/25/2018] [Accepted: 12/27/2018] [Indexed: 01/22/2023] Open
Abstract
Epigenetic dysregulation plays a crucial role in cardiovascular diseases. Previously, we reported that acetyltransferase p300 (ATp300) inhibitor L002 prevents hypertension‐induced cardiac hypertrophy and fibrosis in a murine model. In this short communication, we show that treatment of hypertensive mice with ATp300‐specific small molecule inhibitor L002 or C646 reverses hypertension‐induced left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction, without reducing elevated blood pressures. Biochemically, treatment with L002 and C646 also reverse hypertension‐induced histone acetylation and myofibroblast differentiation in murine ventricles. Our results confirm and extend the role of ATp300, a major epigenetic regulator, in the pathobiology of cardiac hypertrophy and fibrosis. Most importantly, we identify the efficacies of ATp300 inhibitors C646 and L002 in reversing hypertension‐induced cardiac hypertrophy and fibrosis, and discover new anti‐hypertrophic and anti‐fibrotic candidates.
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Affiliation(s)
- Rahul Rai
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
| | - Tianjiao Sun
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
| | - Veronica Ramirez
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
| | - Elizabeth Lux
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
| | - Mesut Eren
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
| | - Douglas E Vaughan
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
| | - Asish K Ghosh
- Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL
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Jia C, Zhang F, Zhu Y, Qi X, Wang Y. Public data mining plus domestic experimental study defined involvement of the old-yet-uncharacterized gene matrix-remodeling associated 7 (MXRA7) in physiopathology of the eye. Gene 2017; 632:43-49. [PMID: 28847716 DOI: 10.1016/j.gene.2017.08.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/12/2017] [Accepted: 08/23/2017] [Indexed: 12/22/2022]
Abstract
Matrix-remodeling associated 7 (MXRA7) gene was first reported in 2002 and named so for its co-expression with several genes known to relate with matrix-remodeling. However, not any studies had been intentionally performed to characterize this gene. We started defining the functions of MXRA7 by integrating bioinformatics analysis and experimental study. Data mining of MXRA7 expression in BioGPS, Gene Expression Omnibus and EurExpress platforms highlighted high level expression of Mxra7 in murine ocular tissues. Real-time PCR was employed to measure Mxra7 mRNA in tissues of adult C57BL/6 mice and demonstrated that Mxra7 was preferentially expressed at higher level in retina, corneas and lens than in other tissues. Then the inflammatory corneal neovascularization (CorNV) model and fungal corneal infections were induced in Balb/c mice, and mRNA levels of Mxra7 as well as several matrix-remodeling related genes (Mmp3, Mmp13, Ecm1, Timp1) were monitored with RT-PCR. The results demonstrated a time-dependent Mxra7 under-expression pattern (U-shape curve along timeline), while all other matrix-remodeling related genes manifested an opposite changes pattern (dome-shape curve). When limited data from BioGPS concerning human MXRA7 gene expression in human tissues were looked at, it was found that ocular tissue was also the one expressing highest level of MXRA7. To conclude, integrative assay of MXRA7 gene expression in public databank as well as domestic animal models revealed a selective high expression MXRA7 in murine and human ocular tissues, and its change patterns in two corneal disease models implied that MXRA7 might play a role in pathological processes or diseases involving injury, neovascularization and would healing.
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Affiliation(s)
- Changkai Jia
- Shandong Provincial Key Lab of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Feng Zhang
- Eye Clinic, Linyi People's Hospital, Linyi, China
| | - Ying Zhu
- Eye Hospital, Institute & School of Optometry and Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Xia Qi
- Shandong Provincial Key Lab of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China
| | - Yiqiang Wang
- Shandong Provincial Key Lab of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China; Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
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Abstract
The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease (CKD)-mineral bone disorder (MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.
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Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway. J Transl Med 2014; 94:1068-82. [PMID: 25068653 DOI: 10.1038/labinvest.2014.100] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 06/04/2014] [Accepted: 06/05/2014] [Indexed: 12/31/2022] Open
Abstract
During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-κB pathway. Oxidative stress induces the expression and secretion of TGF-β1 and TGF-β2 and p38 MAPK phosphorylation. Downregulation of TGF-β1 and TGF-β2 by siRNA technology abolished the H2O2-induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-β secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-β-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.
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Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide. PLoS One 2014; 9:e99378. [PMID: 24905361 PMCID: PMC4048316 DOI: 10.1371/journal.pone.0099378] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 05/13/2014] [Indexed: 02/06/2023] Open
Abstract
Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.
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Zhao H, Dong Y, Tian X, Tan TK, Liu Z, Zhao Y, Zhang Y, Harris DCH, Zheng G. Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases. World J Nephrol 2013; 2:84-89. [PMID: 24255890 PMCID: PMC3832915 DOI: 10.5527/wjn.v2.i3.84] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 08/15/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial–mesenchymal transition (EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, has been shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β (TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.
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Jourdan-LeSaux C, Zhang J, Lindsey ML. Extracellular matrix roles during cardiac repair. Life Sci 2010; 87:391-400. [PMID: 20670633 PMCID: PMC2946433 DOI: 10.1016/j.lfs.2010.07.010] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 06/30/2010] [Accepted: 07/16/2010] [Indexed: 02/06/2023]
Abstract
The cardiac extracellular matrix (ECM) provides a platform for cells to maintain structure and function, which in turn maintains tissue function. In response to injury, the ECM undergoes remodeling that involves synthesis, incorporation, and degradation of matrix proteins, with the net outcome determined by the balance of these processes. The major goals of this review are a) to serve as an initial resource for students and investigators new to the cardiac ECM remodeling field, and b) to highlight a few of the key exciting avenues and methodologies that have recently been explored. While we focus on cardiac injury and responses of the left ventricle (LV), the mechanisms reviewed here have pathways in common with other wound healing models.
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Affiliation(s)
- Claude Jourdan-LeSaux
- Division of Cardiology, Department of Medicine, The University of Texas Health Science Center at San Antonio
| | - Jianhua Zhang
- Division of Cardiology, Department of Medicine, The University of Texas Health Science Center at San Antonio
| | - Merry L. Lindsey
- Division of Cardiology, Department of Medicine, The University of Texas Health Science Center at San Antonio
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Lindsey ML, Borg TK. Understanding the role of the extracellular matrix in cardiovascular development and disease: where do we go from here? J Mol Cell Cardiol 2009; 48:431-2. [PMID: 19781548 DOI: 10.1016/j.yjmcc.2009.09.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2009] [Accepted: 09/15/2009] [Indexed: 12/31/2022]
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