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Zhou W, Fang J, Jia Q, Meng H, Liu F, Mao J. Transcription factor specificity protein (SP) family in renal physiology and diseases. PeerJ 2025; 13:e18820. [PMID: 39850832 PMCID: PMC11756367 DOI: 10.7717/peerj.18820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 12/15/2024] [Indexed: 01/25/2025] Open
Abstract
Dysregulated specificity proteins (SPs), members of the C2H2 zinc-finger family, are crucial transcription factors (TFs) with implications for renal physiology and diseases. This comprehensive review focuses on the role of SP family members, particularly SP1 and SP3, in renal physiology and pathology. A detailed analysis of their expression and cellular localization in the healthy human kidney is presented, highlighting their involvement in fatty acid metabolism, electrolyte regulation, and the synthesis of important molecules. The review also delves into the diverse roles of SPs in various renal diseases, including renal ischemia/reperfusion injury, diabetic nephropathy, renal interstitial fibrosis, and lupus nephritis, elucidating their molecular mechanisms and potential as therapeutic targets. The review further discusses pharmacological modulation of SPs and its implications for treatment. Our findings provide a comprehensive understanding of SPs in renal health and disease, offering new avenues for targeted therapeutic interventions and precision medicine in nephrology.
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Affiliation(s)
- Wei Zhou
- Department of Nephrology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Jiaxi Fang
- Department of Ultrasound, Taizhou Central Hospital, Taizhou, Zhejiang, China
| | - Qingqing Jia
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Hanyan Meng
- Department of Nephrology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Fei Liu
- Department of Nephrology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Jianhua Mao
- Department of Nephrology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
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Tan RJ, Liu Y. Matrix metalloproteinases in kidney homeostasis and diseases: an update. Am J Physiol Renal Physiol 2024; 327:F967-F984. [PMID: 39361724 PMCID: PMC11687849 DOI: 10.1152/ajprenal.00179.2024] [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: 06/20/2024] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 10/05/2024] Open
Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease, and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.
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Affiliation(s)
- Roderick J Tan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States
| | - Youhua Liu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Brandt S, Bernhardt A, Häberer S, Wolters K, Gehringer F, Reichardt C, Krause A, Geffers R, Kahlfuß S, Jeron A, Bruder D, Lindquist JA, Isermann B, Mertens PR. Comparative Analysis of Acute Kidney Injury Models and Related Fibrogenic Responses: Convergence on Methylation Patterns Regulated by Cold Shock Protein. Cells 2024; 13:367. [PMID: 38474331 PMCID: PMC10930537 DOI: 10.3390/cells13050367] [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: 12/29/2023] [Revised: 02/02/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Fibrosis is characterized by excessive extracellular matrix formation in solid organs, disrupting tissue architecture and function. The Y-box binding protein-1 (YB-1) regulates fibrosis-related genes (e.g., Col1a1, Mmp2, and Tgfβ1) and contributes significantly to disease progression. This study aims to identify fibrogenic signatures and the underlying signaling pathways modulated by YB-1. METHODS Transcriptomic changes associated with matrix gene patterns in human chronic kidney diseases and murine acute injury models were analyzed with a focus on known YB-1 targets. Ybx1-knockout mouse strains (Ybx1ΔRosaERT+TX and Ybx1ΔLysM) were subjected to various kidney injury models. Fibrosis patterns were characterized by histopathological staining, transcriptome analysis, qRT-PCR, methylation analysis, zymography, and Western blotting. RESULTS Integrative transcriptomic analyses revealed that YB-1 is involved in several fibrogenic signatures related to the matrisome, the WNT, YAP/TAZ, and TGFß pathways, and regulates Klotho expression. Changes in the methylation status of the Klotho promoter by specific methyltransferases (DNMT) are linked to YB-1 expression, extending to other fibrogenic genes. Notably, kidney-resident cells play a significant role in YB-1-modulated fibrogenic signaling, whereas infiltrating myeloid immune cells have a minimal impact. CONCLUSIONS YB-1 emerges as a master regulator of fibrogenesis, guiding DNMT1 to fibrosis-related genes. This highlights YB-1 as a potential target for epigenetic therapies interfering in this process.
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Affiliation(s)
- Sabine Brandt
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Anja Bernhardt
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Saskia Häberer
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
| | - Katharina Wolters
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
| | - Fabian Gehringer
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Charlotte Reichardt
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Anna Krause
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Robert Geffers
- Genome Analytics Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
| | - Sascha Kahlfuß
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Andreas Jeron
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
- Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Research Group Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
| | - Dunja Bruder
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
- Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Research Group Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
| | - Jonathan A. Lindquist
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig University, 04103 Leipzig, Germany;
| | - Peter R. Mertens
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.B.); (A.B.); (S.H.); (F.G.); (C.R.); (A.K.); (J.A.L.)
- Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany; (S.K.); (A.J.); (D.B.)
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke University, 39120 Magdeburg, Germany
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Fava A, Buyon J, Magder L, Hodgin J, Rosenberg A, Demeke DS, Rao DA, Arazi A, Celia AI, Putterman C, Anolik JH, Barnas J, Dall’Era M, Wofsy D, Furie R, Kamen D, Kalunian K, James JA, Guthridge J, Atta MG, Monroy Trujillo J, Fine D, Clancy R, Belmont HM, Izmirly P, Apruzzese W, Goldman D, Berthier CC, Hoover P, Hacohen N, Raychaudhuri S, Davidson A, Diamond B, Petri M. Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis. JCI Insight 2024; 9:e172569. [PMID: 38258904 PMCID: PMC10906224 DOI: 10.1172/jci.insight.172569] [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: 05/25/2023] [Accepted: 12/06/2023] [Indexed: 01/24/2024] Open
Abstract
Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.
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Affiliation(s)
- Andrea Fava
- Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Jill Buyon
- New York University School of Medicine, New York, New York, USA
| | | | - Jeff Hodgin
- University of Michigan, Ann Arbor, Michigan, USA
| | - Avi Rosenberg
- Division of Renal Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Deepak A. Rao
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Maryland, USA
| | - Arnon Arazi
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | - Alessandra Ida Celia
- Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
- Università La Sapienza, Rome, Italy
| | - Chaim Putterman
- Albert Einstein College of Medicine, New York, New York, USA
- Azrieli Faculty of Medicine of Bar-Ilan University, Zefat, Israel
| | | | | | - Maria Dall’Era
- University of California, San Francisco, San Francisco, California, USA
| | - David Wofsy
- University of California, San Francisco, San Francisco, California, USA
| | - Richard Furie
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | - Diane Kamen
- Medical University of South Carolina, Charleston, South Carolina, USA
| | | | - Judith A. James
- Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Joel Guthridge
- Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Mohamed G. Atta
- Division of Nephrology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Derek Fine
- Division of Nephrology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Robert Clancy
- New York University School of Medicine, New York, New York, USA
| | | | - Peter Izmirly
- New York University School of Medicine, New York, New York, USA
| | - William Apruzzese
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Maryland, USA
| | - Daniel Goldman
- Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | | | | | - Soumya Raychaudhuri
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Maryland, USA
- Broad Institute, Boston, Maryland, USA
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
| | - Anne Davidson
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | - Betty Diamond
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | | | - Michelle Petri
- Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
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5
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Sarray S, Lamine LB, Dallel M, Ezzidi I, Sellami N, Turki A, Moustafa AEEA, Mtiraoui N. Association of matrix metalloproteinase-2 gene variants with diabetic nephropathy risk. J Gene Med 2023; 25:e3553. [PMID: 37312425 DOI: 10.1002/jgm.3553] [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: 02/16/2023] [Revised: 05/11/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Diabetic nephropathy is a highly destructive microvascular complication of diabetes. Genetic predisposition is involved in the pathogenesis of diabetic nephropathy, with multiple allelic polymorphisms associated with the development and progression of the disease, thereby increasing the overall risk. To date, no study is available that shows the association of matrix metalloproteinase-2 (MMP-2) gene polymorphisms with diabetic nephropathy risk. Thus, we investigated the potential genetic influence of MMP-2 promoter variants in the development of diabetic nephropathy in type 2 diabetic patients. METHODS In total, 726 type 2 diabetic patients and 310 healthy controls were included in the study and genotyped for MMP-2, -1306C/T, -790T/G, -1575G/T and -735C/T by real-time PCR. The analysis of the outcomes was performed assuming three genetic models. The threshold for statistical significance was set at 0.05. RESULTS The results showed that the minor allele frequency of the -790T/G variant was significantly higher in patients with and without nephropathy compared to controls. Furthermore, the distribution analysis revealed a significant association of the -790T/G variant, in all genetic models, with increased risk of diabetic nephropathy that persisted after adjusting for key covariates. No significant associations between MMP-2, -1306C/T, -1575G/T, -735C/T and the risk of diabetic nephropathy were detected. Haplotype analysis identified two risk haplotypes GCGC and GTAC associated with diabetic nephropathy. CONCLUSIONS The present study is the first to demonstrate the allelic and genotypic association of the MMP-2-790T/G variant and two haplotypes with an increased risk of diabetic nephropathy in a Tunisian population with type 2 diabetes.
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Affiliation(s)
- Sameh Sarray
- Arabian Gulf University, Manama, Bahrain
- Faculty of Sciences, University Tunis EL Manar, Tunis, Tunisia
| | - Laila Ben Lamine
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Meriem Dallel
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Intissar Ezzidi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia
| | - Nejla Sellami
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Amira Turki
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | | | - Nabil Mtiraoui
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia
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Laget J, Duranton F, Argilés À, Gayrard N. Renal insufficiency and chronic kidney disease – Promotor or consequence of pathological post-translational modifications. Mol Aspects Med 2022; 86:101082. [DOI: 10.1016/j.mam.2022.101082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/27/2022] [Accepted: 02/03/2022] [Indexed: 12/12/2022]
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Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in kidney disease. Adv Clin Chem 2021; 105:141-212. [PMID: 34809827 DOI: 10.1016/bs.acc.2021.02.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Matrix metalloproteinases (MMPs) are a group of zinc and calcium endopeptidases which cleave extracellular matrix (ECM) proteins. They are also involved in the degradation of cell surface components and regulate multiple cellular processes, cell to cell interactions, cell proliferation, and cell signaling pathways. MMPs function in close interaction with the endogenous tissue inhibitors of matrix metalloproteinases (TIMPs), both of which regulate cell turnover, modulate various growth factors, and participate in the progression of tissue fibrosis and apoptosis. The multiple roles of MMPs and TIMPs are continuously elucidated in kidney development and repair, as well as in a number of kidney diseases. This chapter focuses on the current findings of the significance of MMPs and TIMPs in a wide range of kidney diseases, whether they result from kidney tissue changes, hemodynamic alterations, tubular epithelial cell apoptosis, inflammation, or fibrosis. In addition, the potential use of these endopeptidases as biomarkers of renal dysfunction and as targets for therapeutic interventions to attenuate kidney disease are also explored in this review.
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Ali MAM, Garcia-Vilas JA, Cromwell CR, Hubbard BP, Hendzel MJ, Schulz R. Matrix metalloproteinase-2 mediates ribosomal RNA transcription by cleaving nucleolar histones. FEBS J 2021; 288:6736-6751. [PMID: 34101354 DOI: 10.1111/febs.16061] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/09/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023]
Abstract
Cell proliferation and survival require continuous ribosome biogenesis and protein synthesis. Genes encoding ribosomal RNA are physically located in a specialized substructure within the nucleus known as the nucleolus, which has a central role in the biogenesis of ribosomes. Matrix metalloproteinase-2 was previously detected in the nucleus, however, its role there is elusive. Herein we report that matrix metalloproteinase-2 resides within the nucleolus to regulate ribosomal RNA transcription. Matrix metalloproteinase-2 is enriched at the promoter region of ribosomal RNA gene repeats, and its inhibition downregulates preribosomal RNA transcription. The N-terminal tail of histone H3 is clipped by matrix metalloproteinase-2 in the nucleolus, which is associated with increased ribosomal RNA transcription. Knocking down/out matrix metalloproteinase-2, or inhibiting its activity, prevents histone H3 cleavage and reduces both ribosomal RNA transcription and cell proliferation. In addition to the known extracellular roles of matrix metalloproteinase-2 in tumor growth, our data reveal an epigenetic mechanism whereby intranucleolar matrix metalloproteinase-2 regulates cell proliferation through histone clipping and facilitation of ribosomal RNA transcription.
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Affiliation(s)
- Mohammad A M Ali
- Department of Pediatrics, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada.,Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Binghamton, NY, USA
| | - Javier A Garcia-Vilas
- Department of Pediatrics, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada.,Department of Pharmacology, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
| | - Christopher R Cromwell
- Department of Pharmacology, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
| | - Basil P Hubbard
- Department of Pharmacology, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
| | - Michael J Hendzel
- Department of Oncology, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
| | - Richard Schulz
- Department of Pediatrics, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada.,Department of Pharmacology, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
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9
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Silva FS, Canêdo VSR, Abreu BJ, Oliveira MF. Responses of matrix metalloproteinases to hyperbaric oxygen treatment: changing for good or ill? Connect Tissue Res 2021; 62:249-262. [PMID: 32900238 DOI: 10.1080/03008207.2020.1821675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Background: Hyperbaric oxygen (HBO2) is currently emerging as a promising therapeutic option for diseases involving impaired tissue repair and remodeling. In this regard, HBO2 has been shown to modulate signaling pathways responsible for matrix metalloproteinases (MMPs) regulation, which makes the MMPs interesting targets for investigation. However, the understanding regarding how HBO2 treatment affects the expression and activity of the MMP family members in different tissues and diseases needs to be clarified. The precise roles of MMPs in the physiopathology of various tissue repair disorders also remain unclear. Because of potential off-target systemic effects of the HBO2 on MMPs, researchers and physicians should carefully consider whether their patients could be affected adversely by HBO2 exposure. Aims: This narrative review provides an overview of MMP biology (structure, function, and regulation) and summarizes available data showing how MMPs respond to HBO2 in different tissues and pathologies, also highlighting possible mechanisms.
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Affiliation(s)
- Flávio S Silva
- Department of Health Sciences, Federal Rural University of the Semi-Arid (UFERSA), Mossoró, Brazil
| | - Vítor S R Canêdo
- Department of Health Sciences, Federal Rural University of the Semi-Arid (UFERSA), Mossoró, Brazil
| | - Bento J Abreu
- Department of Morphology, Federal University of Rio Grande Do Norte (UFRN), Natal, Brazil
| | - Moacir F Oliveira
- Department of Animal Sciences, Federal Rural University of the Semi-Arid (UFERSA), Mossoró, Brazil
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10
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Cruz JDO, Silva AO, Ribeiro JM, Luizon MR, Ceron CS. Epigenetic Regulation of the N-Terminal Truncated Isoform of Matrix Metalloproteinase-2 (NTT-MMP-2) and Its Presence in Renal and Cardiac Diseases. Front Genet 2021; 12:637148. [PMID: 33732288 PMCID: PMC7959838 DOI: 10.3389/fgene.2021.637148] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/26/2021] [Indexed: 12/19/2022] Open
Abstract
Several clinical and experimental studies have documented a compelling and critical role for the full-length matrix metalloproteinase-2 (FL-MMP-2) in ischemic renal injury, progressive renal fibrosis, and diabetic nephropathy. A novel N-terminal truncated isoform of MMP-2 (NTT-MMP-2) was recently discovered, which is induced by hypoxia and oxidative stress by the activation of a latent promoter located in the first intron of the MMP2 gene. This NTT-MMP-2 isoform is enzymatically active but remains intracellular in or near the mitochondria. In this perspective article, we first present the findings about the discovery of the NTT-MMP-2 isoform, and its functional and structural differences as compared with the FL-MMP-2 isoform. Based on publicly available epigenomics data from the Encyclopedia of DNA Elements (ENCODE) project, we provide insights into the epigenetic regulation of the latent promoter located in the first intron of the MMP2 gene, which support the activation of the NTT-MMP-2 isoform. We then focus on its functional assessment by covering the alterations found in the kidney of transgenic mice expressing the NTT-MMP-2 isoform. Next, we highlight recent findings regarding the presence of the NTT-MMP-2 isoform in renal dysfunction, in kidney and cardiac diseases, including damage observed in aging, acute ischemia-reperfusion injury (IRI), chronic kidney disease, diabetic nephropathy, and human renal transplants with delayed graft function. Finally, we briefly discuss how our insights may guide further experimental and clinical studies that are needed to elucidate the underlying mechanisms and the role of the NTT-MMP-2 isoform in renal dysfunction, which may help to establish it as a potential therapeutic target in kidney diseases.
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Affiliation(s)
- Juliana de Oliveira Cruz
- Graduate Program in Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.,Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Alessandra O Silva
- Department of Food and Drugs, Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Jessyca M Ribeiro
- Department of Food and Drugs, Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Marcelo R Luizon
- Graduate Program in Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.,Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Carla S Ceron
- Department of Biological Sciences, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
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11
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Ngowi EE, Sarfraz M, Afzal A, Khan NH, Khattak S, Zhang X, Li T, Duan SF, Ji XY, Wu DD. Roles of Hydrogen Sulfide Donors in Common Kidney Diseases. Front Pharmacol 2020; 11:564281. [PMID: 33364941 PMCID: PMC7751760 DOI: 10.3389/fphar.2020.564281] [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: 05/21/2020] [Accepted: 09/30/2020] [Indexed: 12/15/2022] Open
Abstract
Hydrogen sulfide (H2S) plays a key role in the regulation of physiological processes in mammals. The decline in H2S level has been reported in numerous renal disorders. In animal models of renal disorders, treatment with H2S donors could restore H2S levels and improve renal functions. H2S donors suppress renal dysfunction by regulating autophagy, apoptosis, oxidative stress, and inflammation through multiple signaling pathways, such as TRL4/NLRP3, AMP-activated protein kinase/mammalian target of rapamycin, transforming growth factor-β1/Smad3, extracellular signal-regulated protein kinases 1/2, mitogen-activated protein kinase, and nuclear factor kappa B. In this review, we summarize recent developments in the effects of H2S donors on the treatment of common renal diseases, including acute/chronic kidney disease, renal fibrosis, unilateral ureteral obstruction, glomerulosclerosis, diabetic nephropathy, hyperhomocysteinemia, drug-induced nephrotoxicity, metal-induced nephrotoxicity, and urolithiasis. Novel H2S donors can be designed and applied in the treatment of common renal diseases.
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Affiliation(s)
- Ebenezeri Erasto Ngowi
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Department of Biological Sciences, Faculty of Science, Dar es Salaam University College of Education, Dar es Salaam, Tanzania
| | - Muhammad Sarfraz
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Kaifeng Municipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, China
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Attia Afzal
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- College of Pharmacy, Henan University, Kaifeng, China
| | - Saadullah Khattak
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
| | - Xin Zhang
- College of Pharmacy, Henan University, Kaifeng, China
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Tao Li
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
| | - Shao-Feng Duan
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- College of Pharmacy, Henan University, Kaifeng, China
- Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Xin-Ying Ji
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- Diseases and Bio-Safety, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Dong-Dong Wu
- School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
- School of Stomatology, Henan University, Kaifeng, China
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12
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Margetts PJ, Bonniaud P. Basic Mechanisms and Clinical Implications of Peritoneal Fibrosis. Perit Dial Int 2020. [DOI: 10.1177/089686080302300604] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Peter J. Margetts
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Philippe Bonniaud
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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13
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Matrix Metalloproteinases in Diabetic Kidney Disease. J Clin Med 2020; 9:jcm9020472. [PMID: 32046355 PMCID: PMC7073625 DOI: 10.3390/jcm9020472] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/30/2020] [Accepted: 02/01/2020] [Indexed: 12/11/2022] Open
Abstract
Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effect.
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14
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Paunas FTI, Finne K, Leh S, Osman TAH, Marti HP, Berven F, Vikse BE. Characterization of glomerular extracellular matrix in IgA nephropathy by proteomic analysis of laser-captured microdissected glomeruli. BMC Nephrol 2019; 20:410. [PMID: 31726998 PMCID: PMC6854890 DOI: 10.1186/s12882-019-1598-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 10/23/2019] [Indexed: 12/29/2022] Open
Abstract
Background IgA nephropathy (IgAN) involves mesangial matrix expansion, but the proteomic composition of this matrix is unknown. The present study aimed to characterize changes in extracellular matrix in IgAN. Methods In the present study we used mass spectrometry-based proteomics in order to quantitatively compare protein abundance between glomeruli of patients with IgAN (n = 25) and controls with normal biopsy findings (n = 15). Results Using a previously published paper by Lennon et al. and cross-referencing with the Matrisome database we identified 179 extracellular matrix proteins. In the comparison between IgAN and controls, IgAN glomeruli showed significantly higher abundance of extracellular matrix structural proteins (e.g periostin, vitronectin, and extracellular matrix protein 1) and extracellular matrix associated proteins (e.g. azurocidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase-9 and matrix metalloproteinase 2). Periostin (fold change 3.3) and azurocidin (3.0) had the strongest fold change between IgAN and controls; periostin was also higher in IgAN patients who progressed to ESRD as compared to patients who did not. Conclusion IgAN is associated with widespread changes of the glomerular extracellular matrix proteome. Proteins important in glomerular sclerosis or inflammation seem to be most strongly increased and periostin might be an important marker of glomerular damage in IgAN.
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Affiliation(s)
- Flavia Teodora Ioana Paunas
- Department of Medicine, Haugesund Hospital, Haugesund, Norway. .,Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Kenneth Finne
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Sabine Leh
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | | | - Hans-Peter Marti
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Frode Berven
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Bjørn Egil Vikse
- Department of Medicine, Haugesund Hospital, Haugesund, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
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15
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Zakiyanov O, Kalousová M, Zima T, Tesař V. Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal. Kidney Blood Press Res 2019; 44:298-330. [PMID: 31185475 DOI: 10.1159/000499876] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/10/2019] [Indexed: 11/19/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases within the metzincin protein family that not only cleave extracellular matrix (ECM) components, but also process the non-ECM molecules, including various growth factors and their binding proteins. MMPs participate in cell to ECM interactions, and MMPs are known to be involved in cell proliferation mechanisms and most probably apoptosis. These proteinases are grouped into six classes: collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs, and other MMPs. Various mechanisms regulate the activity of MMPs, inhibition by tissue inhibitors of metalloproteinases being the most important. In the kidney, intrinsic glomerular cells and tubular epithelial cells synthesize several MMPs. The measurement of circulating MMPs can provide valuable information in patients with kidney diseases. They play an important role in many renal diseases, both acute and chronic. This review attempts to summarize the current knowledge of MMPs in the kidney and discusses recent data from patient and animal studies with reference to specific diseases. A better understanding of the MMPs' role in renal remodeling may open the way to new interventions favoring deleterious renal changes in a number of kidney diseases.
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Affiliation(s)
- Oskar Zakiyanov
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia,
| | - Marta Kalousová
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Tomáš Zima
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Vladimír Tesař
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
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16
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Bülow RD, Boor P. Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold. J Histochem Cytochem 2019; 67:643-661. [PMID: 31116062 DOI: 10.1369/0022155419849388] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Kidney fibrosis is the common histological end-point of progressive, chronic kidney diseases (CKDs) regardless of the underlying etiology. The hallmark of renal fibrosis, similar to all other organs, is pathological deposition of extracellular matrix (ECM). Renal ECM is a complex network of collagens, elastin, and several glycoproteins and proteoglycans forming basal membranes and interstitial space. Several ECM functions beyond providing a scaffold and organ stability are being increasingly recognized, for example, in inflammation. ECM composition is determined by the function of each of the histological compartments of the kidney, that is, glomeruli, tubulo-interstitium, and vessels. Renal ECM is a dynamic structure undergoing remodeling, particularly during fibrosis. From a clinical perspective, ECM proteins are directly involved in several rare renal diseases and indirectly in CKD progression during renal fibrosis. ECM proteins could serve as specific non-invasive biomarkers of fibrosis and scaffolds in regenerative medicine. The gold standard and currently only specific means to measure renal fibrosis is renal biopsy, but new diagnostic approaches are appearing. Here, we discuss the localization, function, and remodeling of major renal ECM components in healthy and diseased, fibrotic kidneys and the potential use of ECM in diagnostics of renal fibrosis and in tissue engineering.
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Affiliation(s)
- Roman David Bülow
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Peter Boor
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.,Department of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany
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17
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Zakiyanov O, Chocová Z, Hrušková Z, Hladinová Z, Kalousová M, Maličková K, Vachek J, Wurmová P, Kříha V, Zima T, Tesař V. Matrix Metalloproteinases and Their Tissue Inhibitors: an Evaluation of Novel Biomarkers in ANCA-Associated Vasculitis. Folia Biol (Praha) 2019; 65:227-236. [PMID: 32362306 DOI: 10.14712/fb2019065050227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play an important role in both inflammation with subsequent fibrosis and in repair and healing in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We evaluated the circulating levels of MMPs, including pregnancy-associated plasma protein A (PAPP-A), and TIMPs in patients with AAV. PAPP-A, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2 and selected parameters were measured in 100 AAV patients (36 patients with active disease and 64 patients in remission) and 34 healthy subjects. The levels of MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2, and PAPP-A in AAV were all found to be different to those of the controls. The MMP-7 and PAPP-A concentrations were increased in active disease in comparison to the controls (MMP-7: 13 ±.7 vs. 2 ± 0.6 ng/ml, PAPP-A: 14 ± 18 vs. 6.8 ± 2.6 ng/ml, both P < 0.005). The MMP-2 and TIMP-2 levels were increased in remission when compared to the controls (MMP-2: 242 ± 50 ng/ml vs. 212 ± 26 ng /ml, TIMP-2: 82 ± 14 ng/ml vs. 68 ± 93 ng/ml) and to the active AAV (MMP-2: 242 ± 50 vs. 219 ± 54 ng/ml, TIMP-2: 82 ± 14 ng/ml vs. 73 ± 15 ng/ml, all P < 0.005). MMP-3, MMP-7, TIMP-1, and PAPP-A correlated with serum creatinine. The serum levels of MMPs, TIMPs and PAPP-A are all altered in AAV. MMP-2, MMP-7 and TIMP-2 appear to be promising markers in distinguishing active AAV from remission. MMP-3, MMP-7, TIMP-1, and PAPP-A are associated with kidney function in AAV. Further studies are needed to delineate the exact roles of circulating MMPs, TIMPs and PAPP-A in patients with AAV.
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Affiliation(s)
- O Zakiyanov
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Z Chocová
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Z Hrušková
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Z Hladinová
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - M Kalousová
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - K Maličková
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - J Vachek
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - P Wurmová
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - V Kříha
- Institute of Radiation Oncology, Bulovka Hospital, Prague, Czech Republic
| | - T Zima
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - V Tesař
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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18
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Wurm S, Steege A, Rom-Jurek EM, van Roeyen CR, Kurtz A, Banas B, Banas MC. CCR7 Is Important for Mesangial Cell Physiology and Repair. J Histochem Cytochem 2017; 66:7-22. [PMID: 29077526 DOI: 10.1369/0022155417737975] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The homeostatic chemokine receptor CCR7 serves as key molecule in lymphocyte homing into secondary lymphoid tissues. Previous experiments from our group identified CCR7 also to be expressed by human mesangial cells. Exposing cultured human mesangial cells to the receptor ligand CCL21 revealed a positive effect on these cells regarding proliferation, migration, and survival. In the present study, we localized CCR7 and CCL21 during murine nephrogenesis. Analyzing wild-type and CCR7 deficient (CCR7-/-) mice, we observed a retarded glomerulogenesis during renal development and a significantly decreased mesangial cellularity in adult CCR7-/- mice, as a consequence of less mesangial cell proliferation between embryonic day E17.5 and week 5 postpartum. Cell proliferation assays and cell-wounding experiments confirmed reduced proliferative and migratory properties of mesangial cells cultured from CCR7-/- kidneys. To further emphasize the role of CCR7 as important factor for mesangial biology, we examined the chemokine receptor expression in rats after induction of a mesangioproliferative glomerulonephritis. Here, we demonstrated for the first time that extra- and intraglomerular mesangial cells that were CCR7-negative in control rats exhibited a strong CCR7 expression during the phase of mesangial repopulation and proliferation.
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Affiliation(s)
- Simone Wurm
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Andreas Steege
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Eva-Maria Rom-Jurek
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.,Department of Gynaecology and Obstetrics, University Hospital Regensburg, Regensburg, Germany
| | - Claudia R van Roeyen
- Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | - Armin Kurtz
- Institute of Physiology, University of Regensburg, Regensburg, Germany
| | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Miriam C Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
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19
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El Sharkawi FZ, Ewais SM, Fahmy RH, Rashed LA. PTEN and TRAIL genes loaded zein nanoparticles as potential therapy for hepatocellular carcinoma. J Drug Target 2017; 25:513-522. [PMID: 28140697 DOI: 10.1080/1061186x.2017.1289536] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Gene therapy is one of the recent approaches in treatment of hepatocellular carcinoma (HCC). Development of a vector or vehicle that can selectively and efficiently deliver the gene to target cells with minimal toxicity is an urgent demand. In the present study, phosphatase and tensin homolog (PTEN) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) genes were loaded to zein nanoparticles (ZNPs). The formulated PTEN and TRAIL-loaded ZNPs were tested for their in vitro and in vivo potential antitumor efficacy using liver tumor cells (HepG2) and HCC-induced rats as animal model. Also, mRNA expression of p53, VGEF and MMP-2 were carried out as markers of apoptosis, angiogenesis and metastasis in animal liver tissues. The results of the study showed that both PTEN and TRAIL-loaded ZNPs proved anti-proliferative activity against HepG2 cell lines with IC50 values of 0.09, 0.25 µg/ml, respectively. In vivo assay confirmed decrease in mRNA expression of both VEGF and MMP-2 with increased in P53 expression level in liver tissues of the treated animals. Therefore, authors introduced new integration between gene therapy and nanotechnology in the form of PTEN and TRAIL-loaded ZNPs that proved potential to be used in gene therapy for the treatment of HCC.
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Affiliation(s)
- Fathia Zaki El Sharkawi
- a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy , Helwan University , Cairo , Egypt
| | - Shaimaa Mohammed Ewais
- a Department of Biochemistry and Molecular Biology, Faculty of Pharmacy , Helwan University , Cairo , Egypt
| | - Rania Hassan Fahmy
- b Department of Pharmaceutics and Industrial pharmacy, Faculty of Pharmacy , Cairo University , Cairo , Egypt.,c Department of Pharmaceutics, Faculty of Pharmacy , Ahram Canadian University , Giza , Egypt
| | - Laila Ahmed Rashed
- d Department of Biochemistry and Molecular Biology, Faculty of Medicine , Cairo University , Cairo , Egypt
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20
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Erikci A, Ucar G, Yabanoglu-Ciftci S. Role of serotonin in the regulation of renal proximal tubular epithelial cells. Ren Fail 2016; 38:1141-50. [PMID: 27277500 DOI: 10.1080/0886022x.2016.1194165] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
In various renal injuries, tissue damage occurs and platelet activation is observed. Recent studies suggest that some factors, such as serotonin, are released into microenvironment upon platelet activation following renal injury. In the present study, we aimed to investigate whether platelets and platelet-released serotonin are involved in the functional regulation of renal proximal tubular epithelial cells (PTECs). PTECs were obtained by primary cell culture and treated with platelet lysate (PL) (2 × 10(6)/mL, 4 × 10(6)/mL, 8 × 10(6)/mL) or serotonin (1 μM or 5 μM) for 12 or 24 h. Phenotypic transdifferentiation of epithelial cells into myofibroblasts were demonstrated under light microscope and confirmed by the determination of α-smooth muscle actin gene expression. Serotonin and PL were shown to induce epithelial-mesenchymal transdifferentiation of PTECs. After stimulation of PTECs with serotonin or PL, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and collagen-α1 gene expressions, which were reported to be elevated in renal injury, were determined by real-time PCR and found to be upregulated. Expressions of some inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and transforming growth factor-β1 were found to be increased in both protein and gene levels. Recently there is no published report on the effect of serotonin on renal PTECs. Results obtained in this study have lightened the role of serotonin and platelet-mediated effects of serotonin on fibrotic and inflammatory processes in PTECs.
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Affiliation(s)
- Acelya Erikci
- a Department of Biochemistry, Faculty of Pharmacy , Hacettepe University , Ankara , Turkey
| | - Gulberk Ucar
- a Department of Biochemistry, Faculty of Pharmacy , Hacettepe University , Ankara , Turkey
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21
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Cell biology of mesangial cells: the third cell that maintains the glomerular capillary. Anat Sci Int 2016; 92:173-186. [PMID: 26910209 DOI: 10.1007/s12565-016-0334-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 02/14/2016] [Indexed: 10/22/2022]
Abstract
The renal glomerulus consists of glomerular endothelial cells, podocytes, and mesangial cells, which cooperate with each other for glomerular filtration. We have produced monoclonal antibodies against glomerular cells in order to identify different types of glomerular cells. Among these antibodies, the E30 clone specifically recognizes the Thy1.1 molecule expressed on mesangial cells. An injection of this antibody into rats resulted in mesangial cell-specific injury within 15 min, and induced mesangial proliferative glomerulonephritis in a reproducible manner. We examined the role of mesangial cells in glomerular function using several experimental tools, including an E30-induced nephritis model, mesangial cell culture, and the deletion of specific genes. Herein, we describe the characterization of E30-induced nephritis, formation of the glomerular capillary network, mesangial matrix turnover, and intercellular signaling between glomerular cells. New molecules that are involved in a wide variety of mesangial cell functions are also introduced.
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22
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Xu X, Xiao L, Xiao P, Yang S, Chen G, Liu F, Kanwar YS, Sun L. A glimpse of matrix metalloproteinases in diabetic nephropathy. Curr Med Chem 2015; 21:3244-60. [PMID: 25039784 DOI: 10.2174/0929867321666140716092052] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 07/06/2014] [Accepted: 07/11/2014] [Indexed: 12/14/2022]
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
| | | | | | | | | | | | | | - L Sun
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 415800, China..
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Siddesha JM, Valente AJ, Sakamuri SSVP, Gardner JD, Delafontaine P, Noda M, Chandrasekar B. Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK. J Cell Physiol 2014; 229:845-55. [PMID: 24265116 DOI: 10.1002/jcp.24511] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 11/18/2013] [Indexed: 01/01/2023]
Abstract
The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H(2)O(2) generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H(2)O(2) generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms.
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Affiliation(s)
- Jalahalli M Siddesha
- Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana
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The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis? FIBROGENESIS & TISSUE REPAIR 2014; 7:4. [PMID: 24678881 PMCID: PMC3986639 DOI: 10.1186/1755-1536-7-4] [Citation(s) in RCA: 259] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023]
Abstract
Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clinical course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also in the development of new treatments is the lack of markers able to identify and stratify patients with stable versus progressive disease. At the moment renal biopsy is the only means of diagnosing renal interstitial fibrosis. Novel biomarkers should improve diagnosis of a disease, estimate its prognosis and assess the response to treatment, all in a non-invasive manner. Existing markers of CKD do not fully and specifically address these requirements and in particular do not specifically reflect renal fibrosis. The aim of this review is to give an insight of the involvement of the extracellular matrix (ECM) proteins in kidney diseases and as a source of potential novel biomarkers of renal fibrosis. In particular the use of the protein fingerprint technology, that identifies neo-epitopes of ECM proteins generated by proteolytic cleavage by proteases or other post-translational modifications, might identify such novel biomarkers of renal fibrosis.
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Identification of MMP-2 as a novel enhancer of cerebellar granule cell proliferation. Mol Cell Neurosci 2013; 57:63-72. [DOI: 10.1016/j.mcn.2013.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 09/10/2013] [Accepted: 10/04/2013] [Indexed: 01/20/2023] Open
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Kuroda T, Masui M, Notoya M, Ito M, Tamura Y, Okamoto H, Kanaoka E, Shinosaki T. Renoprotective action of a matrix metalloproteinase inhibitor in progressive mesangioproliferative nephritis. NEPHRON EXTRA 2012; 2:133-46. [PMID: 22739248 PMCID: PMC3383302 DOI: 10.1159/000338801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background/Aim Matrix metalloproteinases (MMPs) play pivotal roles in extracellular matrix turnover and are involved in chronic kidney disease. The renoprotective action of a synthetic MMP inhibitor, compound A, was investigated in chronic nephritis. Methods Nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. The effects of compound A on proteinuria, blood urea nitrogen, and matrix-related gene expressions were evaluated. Collagen accumulation, as assessed by periodic acid-Schiff staining and hydroxyproline content, was determined. The integrity of glomerular epithelial cells and glomerular basement membrane was evaluated with desmin immunohistochemistry and electron microscopic detection of anionic charge sites, respectively. Results Treatment with compound A notably attenuated proteinuria, ameliorated blood urea nitrogen, and prevented glomerulosclerosis. Gene upregulation of collagen and transforming growth factor β1 in the cortex was prevented in the treated animals. Glomerular epithelial cell injury was milder, and glomerular basement membrane anionic sites were protected with the treatment. Conclusion A novel MMP inhibitor, compound A, exerts protective effects in progressive glomerulonephritis. Compound A ameliorates various aspects of renal injuries and may have therapeutic potential toward kidney diseases.
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Tan RJ, Liu Y. Matrix metalloproteinases in kidney homeostasis and diseases. Am J Physiol Renal Physiol 2012; 302:F1351-61. [PMID: 22492945 DOI: 10.1152/ajprenal.00037.2012] [Citation(s) in RCA: 177] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have been increasingly linked to both normal physiology and abnormal pathology in the kidney. Collectively able to degrade all components of the extracellular matrix, MMPs were originally thought to antagonize the development of fibrotic diseases solely through digestion of excessive matrix. However, increasing evidence has shown that MMPs play a wide variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP dysregulation in a multitude of renal diseases including acute kidney injury, diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic allograft nephropathy. The goal of this review is to summarize current findings regarding the role of MMPs in kidney diseases as well as the mechanisms of action of this family of proteases.
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Affiliation(s)
- Roderick J Tan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261, USA
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Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, Karliner JS. A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One 2012; 7:e34177. [PMID: 22509276 PMCID: PMC3317925 DOI: 10.1371/journal.pone.0034177] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Accepted: 02/27/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress. METHODOLOGY AND PRINCIPAL FINDINGS Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes. CONCLUSION A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure.
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Affiliation(s)
- David H Lovett
- Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, California, United States of America.
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Czech KA, Bennett M, Devarajan P. Distinct metalloproteinase excretion patterns in focal segmental glomerulosclerosis. Pediatr Nephrol 2011; 26:2179-84. [PMID: 21720805 DOI: 10.1007/s00467-011-1897-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Revised: 03/17/2011] [Accepted: 03/30/2011] [Indexed: 11/28/2022]
Abstract
Metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) degrade type IV collagen, and represent important tissue remodeling enzymes in several kidney disorders. In this study, we measured urinary levels of MMP-2, MMP-9, and the tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in patients with steroid-sensitive nephrotic syndrome (SSNS, n = 18, median age 5) and focal segmental glomerulosclerosis (FSGS, n = 16, median age 15). We found that urinary concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were significantly elevated in FSGS patients as compared to SSNS in both relapse and remission (p < 0.002). Furthermore, urinary levels of these enzymes are increased early on in the FSGS disease process (chronic kidney disease stages 1 and 2). The findings from this pilot study suggest that MMPs and TIMPs have the potential to represent candidate, early non-invasive biomarkers for diagnosis and/or response to therapy. In addition, they may represent therapeutic targets for preventing chronic kidney disease progression in FSGS.
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Affiliation(s)
- Kimberly A Czech
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital and Medical Center, 3333 Burnet Ave, MLC 7022, Cincinnati, OH 45229, USA.
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Roberts-Pilgrim AM, Makareeva E, Myles MH, Besch-Williford CL, Brodeur AC, Walker AL, Leikin S, Franklin CL, Phillips CL. Deficient degradation of homotrimeric type I collagen, α1(I)3 glomerulopathy in oim mice. Mol Genet Metab 2011; 104:373-82. [PMID: 21855382 PMCID: PMC3205245 DOI: 10.1016/j.ymgme.2011.07.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Revised: 07/27/2011] [Accepted: 07/27/2011] [Indexed: 01/15/2023]
Abstract
Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional proα2(I) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal mesangium remains unclear. The recent demonstration of the resistance of homotrimeric type I collagen to cleavage by matrix metalloproteinases (MMPs), led us to investigate the role of MMP-resistance in the glomerulosclerosis of Col1a2-deficient mice. We measured the pre- and post-translational expression of type I collagen and MMPs in glomeruli from heterozygous and homozygous animals. Both the heterotrimeric and homotrimeric isotypes of type I collagen were equally present in whole kidneys of heterozygous mice by immunohistochemistry and biochemical analysis, but the sclerotic glomerular collagen was at least 95-98% homotrimeric, suggesting homotrimeric type I collagen is the pathogenic isotype of type I collagen in glomerular disease. Although steady-state MMP and Col1a1 mRNA levels increased with the disease progression, we found these changes to be a secondary response to the deficient clearance of MMP-resistant homotrimers. Increased renal MMP expression was not sufficient to prevent homotrimeric type I collagen accumulation.
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Affiliation(s)
- Anna M. Roberts-Pilgrim
- Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA. , , and ,
| | - Elena Makareeva
- NICHD, National Institutes of Health, Bethesda, MD 20892, USA. ,
| | - Matthew H. Myles
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri 65211, USA. , ,
| | | | - Amanda C. Brodeur
- Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA. , , and ,
- Department of Child Health, University of Missouri, Columbia, Missouri 65212, USA. ,
| | - Andrew L. Walker
- Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA. , , and ,
| | - Sergey Leikin
- NICHD, National Institutes of Health, Bethesda, MD 20892, USA. ,
| | - Craig L. Franklin
- Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri 65211, USA. , ,
| | - Charlotte L. Phillips
- Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA. , , and ,
- Department of Child Health, University of Missouri, Columbia, Missouri 65212, USA. ,
- Correspondence and Reprint Requests: Charlotte L. Phillips, Ph.D., Associate Professor, Departments of Biochemistry and Child Health, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211 USA, Phone: 1-573-882-5122, Fax: 1-573-882-5635,
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Khan S, Lakhe-Reddy S, McCarty JH, Sorenson CM, Sheibani N, Reichardt LF, Kim JH, Wang B, Sedor JR, Schelling JR. Mesangial cell integrin αvβ8 provides glomerular endothelial cell cytoprotection by sequestering TGF-β and regulating PECAM-1. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:609-20. [PMID: 21281793 DOI: 10.1016/j.ajpath.2010.10.031] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Revised: 09/17/2010] [Accepted: 10/08/2010] [Indexed: 10/18/2022]
Abstract
Integrins are heterodimeric receptors that regulate cell adhesion, migration, and apoptosis. Integrin αvβ8 is most abundantly expressed in kidney and brain, and its major ligand is latent transforming growth factor-β (TGF-β). Kidney αvβ8 localizes to mesangial cells, which appose glomerular endothelial cells and maintain glomerular capillary structure by mechanical and poorly understood paracrine mechanisms. To establish kidney αvβ8 function, mice with homozygous Itgb8 deletion (Itgb8(-/-)) were generated on outbred and C57BL/6 congenic backgrounds. Most Itgb8(-/-) mice died in utero, and surviving Itgb8(-/-) mice failed to gain weight, and rarely survived beyond 6 weeks. A renal glomerular phenotype included azotemia and albuminuria, as well as increased platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, which was surprisingly not associated with conventional functions, such as endothelial cell hyperplasia, hypertrophy, or perivascular inflammation. Itgb8(-/-) mesangial cells demonstrated reduced latent TGF-β binding, resulting in bioactive TGF-β release, which stimulated glomerular endothelial cell apoptosis. Using PECAM-1 gain and loss of function strategies, we show that PECAM-1 provides endothelial cytoprotection against mesangial cell TGF-β. These results clarify a singular mechanism of mesangial-to-endothelial cell cross-talk, whereby mesangial cell αvβ8 homeostatically arbitrates glomerular microvascular integrity by sequestering TGF-β in its latent conformation. Under pathological conditions associated with decreased mesangial cell αvβ8 expression and TGF-β secretion, compensatory PECAM-1 modulation facilitates glomerular endothelial cell survival.
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Affiliation(s)
- Shenaz Khan
- Department of Medicine, Case Western Reserve University and Rammelkamp Center for Research and Education, Cleveland, Ohio, USA
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Liu X, Lü L, Tao BB, Zhou AL, Zhu YC. Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin. Acta Pharmacol Sin 2011; 32:70-8. [PMID: 21206504 PMCID: PMC4003321 DOI: 10.1038/aps.2010.200] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 09/01/2010] [Indexed: 12/17/2022] Open
Abstract
AIM To examine the effects of all-trans retinoic acid (atRA) on renal morphology and function as well as on renal plasminogen activator inhibitor-1 (PAI-1) expression and plasmin activity in rats with 5/6 nephrectomy. METHODS Adult male Sprague Dawley rats were given 5/6 nephrectomy or sham operation. Renal function was measured 2 weeks later. The nephrectomized rats were assigned to groups matched for proteinuria and treated with vehicle or atRA (5 or 10 mg/kg by gastric gavage once daily) for the next 12 weeks. Rats with sham operation were treated with vehicle. At the end of the treatments, kidneys were collected for histological examination, Western blot analysis, and enzymatic activity measurements. RESULTS The 5/6 nephrectomy promoted hypertension, renal dysfunction, and glomerulosclerosis. These changes were significantly reduced in the atRA-treated group. The expressions of PAI-1 and α-smooth muscle actin (α-SMA) were significantly increased in the vehicle-treated nephrectomized rats. Treatment with atRA significantly reduced the expressions of PAI-1 and α-SMA. However, plasmin activity remained unchanged following atRA treatment. CONCLUSION Treatment with atRA ameliorates glomerulosclerosis and improves renal function in rats with 5/6 nephrectomy. This is associated with a decrease in PAI-1 and α-SMA, but not with a change in plasmin activity.
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Affiliation(s)
- Xia Liu
- Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai 200032, China
- Department of Pathophysiology, Nantong University Nantong Medical College, Nantong 226001, China
| | - Lei Lü
- Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Bei-bei Tao
- Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ai-ling Zhou
- Department of Pathophysiology, Nantong University Nantong Medical College, Nantong 226001, China
| | - Yi-chun Zhu
- Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai 200032, China
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Lovett DH, Cheng S, Cape L, Pollock AS, Mertens PR. YB-1 alters MT1-MMP trafficking and stimulates MCF-7 breast tumor invasion and metastasis. Biochem Biophys Res Commun 2010; 398:482-8. [PMID: 20599698 DOI: 10.1016/j.bbrc.2010.06.104] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Accepted: 06/28/2010] [Indexed: 12/11/2022]
Abstract
YB-1 is a member of the cold shock domain family, with complex roles in DNA structure, gene transcription and translation. YB-1 promotes chromosomal instability, and mammary gland transgenic expression induces tumors with 100% penetrance. YB-1 is linked to poor prognosis in breast carcinoma and is a strong predictor of relapse and disease-specific survival. Survival is directly tied to the extent of local invasion and distal metastasis, processes dependent upon the activity of the membrane type I-matrix metalloproteinase, MT1-MMP. Non-invasive MCF-7 breast adenocarcinoma cells were transfected with YB-1/EGFP. YB-1 protein was detected in the invadopodia of cells with a migratory phenotype. There was increased expression of MT1-MMP protein concentrated at the leading edges of motile cells, which were highly invasive in collagen three-dimensional culture. The rates of MT1-MMP protein endocytosis and recycling to the cell surface were elevated in clones expressing higher levels of YB-1 protein. Control MCF-7 cells formed nonfatal, non-invasive, differentiated adenocarcinomas in vivo. MCF-7 cells expressing a twofold increase in YB-1 formed highly anaplastic tumors with local invasion, pulmonary metastases and high lethality. We conclude that YB-1 contributes to the development of an invasive, metastatic breast carcinoma phenotype by enhanced presentation of MT1-MMP at the sites of cellular invasion.
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Affiliation(s)
- David H Lovett
- The Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California, The Northern California Institute for Research and Education, San Francisco, CA 94121, USA.
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Differential glomerular immunoexpression of matrix metalloproteinases MMP-2 and MMP-9 in idiopathic IgA nephropathy and Schoenlein-Henoch nephritis. Folia Histochem Cytobiol 2010; 48:63-7. [DOI: 10.2478/v10042-008-0086-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Peng WH, Tien YC, Huang CY, Huang TH, Liao JC, Kuo CL, Lin YC. Fraxinus rhynchophylla ethanol extract attenuates carbon tetrachloride-induced liver fibrosis in rats via down-regulating the expressions of uPA, MMP-2, MMP-9 and TIMP-1. JOURNAL OF ETHNOPHARMACOLOGY 2010; 127:606-613. [PMID: 20035854 DOI: 10.1016/j.jep.2009.12.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Revised: 12/01/2009] [Accepted: 12/05/2009] [Indexed: 05/28/2023]
Abstract
AIM OF THE STUDY To investigate the effect of Fraxinus rhynchophylla ethanol extract (FR(EtOH)) on liver fibrosis induced by carbon tetrachloride (CCl(4)) in rats. MATERIALS AND METHODS Rat hepatic fibrosis was induced by oral administration of CCl(4). Sixty SD rats were divided randomly into 6 groups: control, CCl(4) group, silymarin group and three FR(EtOH)-treated groups. Except for the rats in control group, all rats were administered orally with CCl(4) (20%, 0.2 mL/100g body weight) twice a week for 8 weeks. Rats in FR(EtOH) groups were treated daily with FR(EtOH) (0.1, 0.5 and 1.0 g/kg, p.o.) throughout the whole experimental period. Liver function parameters (such as activities of serum GOT and GPT levels), activities of liver anti-oxidant enzymes (such as catalase, SOD, GPx) and expressions of uPA, tPA, MMP-2, MMP-9 and TIMP-1, -2, -3, -4 in the liver fibrosis pathway were detected. RESULTS The results showed that FR(EtOH) (0.1, 0.5 and 1.0 g/kg BW) significantly reduced the elevated activities of sGOT and sGPT caused by CCl(4). FR(EtOH) (0.1 and 0.5 g/kg BW) and significantly increased the activities of GSH-Px. The histopathological study showed that FR(EtOH) (0.1 and 0.5 g/kg BW) reduced the incidence of liver lesions, including hepatic cells cloudy swelling, lymphocytes infiltration, cytoplasm vacuolization hepatic necrosis and fibrous connective tissue proliferated induced by CCl(4) in rats. In our study it was showed that CCl(4)-treated group significantly increased the protein levels of uPA, MMP-2, MMP-9 and TIMP-1. FR(EtOH) (0.1 and 0.5 g/kg BW) could inhibit the protein levels of uPA, MMP-2, MMP-9 and TIMP-1. Finally, the amount of esculetin in the FR(EtOH) was 33.54 mg/g extract. CONCLUSIONS Oral administration of FR(EtOH) significantly reduces CCl(4)-induced hepatic fibrosis in rats, probably by exerting a protective effect against hepatocellular fibrosis by its free radical scavenging ability. FR(EtOH) down-regulated the expressions of uPA, MMP-2 and MMP-9 in CCl(4)-induced liver fibrosis in rats.
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Affiliation(s)
- Wen-Huang Peng
- Graduate Institute of Chinese Pharmaceutical Sciences, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
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Garg P, Vijay-Kumar M, Wang L, Gewirtz AT, Merlin D, Sitaraman SV. Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. Am J Physiol Gastrointest Liver Physiol 2009; 296:G175-84. [PMID: 19171847 PMCID: PMC2643910 DOI: 10.1152/ajpgi.90454.2008] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Matrix metalloproteinases (MMP) play an important role in pathogenesis of inflammatory bowel disease (IBD). Two known gelatinases, MMP-2 and MMP-9, are upregulated during IBD. Epithelial-derived MMP-9 is an important mediator of tissue injury in colitis, whereas MMP-2 protects against tissue damage and maintains gut barrier function. It has been suggested that developing strategies to block MMP-9 activity in the gut might be of benefit to IBD. However, given that MMP-2 and MMP-9 are structurally similar, such approaches would also likely inhibit MMP-2. Thus, to gain insight into outcome of inhibiting both MMP-2 and MMP-9, MMP-2(-/-)/MMP-9(-/-) double knockout mice (dKO) lacking both MMP-2 and MMP-9 were used in this study. Three models of murine colitis were used: dextran sodium sulfate (DSS), Salmonella typhimurium (S.T.), and trinitrobenzene sulfonic acid (TNBS). Our data demonstrate that MMP-2 and MMP-9 activities were highly upregulated in wild-type (WT) mice treated with DSS, S.T., or TNBS whereas dKO mice were resistant to the development of colitis. WT mice had extensive inflammation and tissue damage compared with dKO mice as suggested by histological assessment and myeloperoxidase activity. In conclusion, these results suggest an overriding role of MMP-9 in mediating tissue injury compared with the protective role of MMP-2 in development of colitis. Thus inhibition of MMP-9 may be beneficial in treatment of colitis even if resulting in inhibition of MMP-2.
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Affiliation(s)
- Pallavi Garg
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Matam Vijay-Kumar
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Lixin Wang
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Andrew T. Gewirtz
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Didier Merlin
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Shanthi V. Sitaraman
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
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Tveita A, Rekvig OP, Zykova SN. Glomerular matrix metalloproteinases and their regulators in the pathogenesis of lupus nephritis. Arthritis Res Ther 2008; 10:229. [PMID: 19090960 PMCID: PMC2656222 DOI: 10.1186/ar2532] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Lupus nephritis is a major contributor to morbidity and mortality in systemic lupus erythematosus, but little is known about the pathogenic processes that underlie the progressive decay in renal function. A common finding in lupus nephritis is thickening of glomerular basement membranes associated with immune complex deposition. It has been speculated that alterations in the synthesis or degradation of membrane components might contribute to such changes, and thereby to initiation and progression of nephritis through facilitation of immune complex deposition. Matrix metalloproteinases (MMPs) are enzymes that are intimately involved in the turnover of major glomerular basement membrane constituents, including collagen IV and laminins. Alterations in the expression and activity of MMPs have been described in a number of renal diseases, suggesting their relevance to the pathogenesis of various glomerulopathies. The same is true for their natural inhibitors, the tissue inhibitor of metalloproteinase family. Recent data from our group have identified an increase in proteolytic activity within the glomerulus coinciding with the development of proteinuria in the mouse model of systemic lupus erythematosus. (NXB x NZW)F1 Here we review current understanding of MMP/tissue inhibitor of metalloproteinase function within the kidney, and discuss their possible involvement in the development and progression of lupus nephritis.
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Affiliation(s)
- Anders Tveita
- Department of Biochemistry, Medical Faculty, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
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38
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Increased glomerular matrix metalloproteinase activity in murine lupus nephritis. Kidney Int 2008; 74:1150-8. [DOI: 10.1038/ki.2008.308] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Munkert A, Helmchen U, Kemper MJ, Bubenheim M, Stahl RAK, Harendza S. Characterization of the transcriptional regulation of the human MT1-MMP gene and association of risk reduction for focal-segmental glomerulosclerosis with two functional promoter SNPs. Nephrol Dial Transplant 2008; 24:735-42. [PMID: 18927121 DOI: 10.1093/ndt/gfn576] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The matrix metalloproteinase MT1-MMP (MMP-14) is an important player in wound healing, bone development, angiogenesis, inflammation and tumour invasion. MT1-MMP also plays an important role in the development and resolution of experimental kidney diseases. The role of MT1-MMP was investigated for distinction between minimal-change glomerulonephritis (MCGN) and focal-segmental glomerulosclerosis (FSGS) that can sometimes be difficult due to sampling error in renal biopsy. METHODS We defined the transcriptional regulation of the human MT1-MMP and the influence of single nucleotide polymorphisms (SNPs) within its promoter region in renal mesangial cells with reporter gene constructs and gel sift analysis. Genomic DNA from healthy blood donors (n = 500) and from kidney biopsies with defined renal diseases (MCGN: n = 189, FSGS: n = 311) was screened for MT1-MMP promoter SNPs. RESULTS Transcription of MT1-MMP is regulated by two enhancers, an Sp1 binding site and a regulatory region 1 (RR1). RR1 contains an Ets site binding the transcription factors Elf-1 and E1AF but not NFAT. The MT1-MMP promoter contains two SNPs (-378 T/C and -364 G/T) in close vicinity to the RR1. Occurrence of the SNP variant -378 C leads to strong inhibition of nuclear protein binding to the RR1 reducing its enhancer function. Appearance of either variant -378 C or variant -364 T in at least one copy of the MT1-MMP promoter was associated with a significant risk reduction for the development of FSGS (P < 0.048). CONCLUSION Genetic testing for MT1-MMP promoter SNPs could put renal biopsy results into new perspective. An independent study will be required to verify these findings and their possible diagnostic value for differentiation between certain renal diseases.
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Affiliation(s)
- Astrid Munkert
- III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
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Keeling J, Herrera GA. Human matrix metalloproteinases: characteristics and pathologic role in altering mesangial homeostasis. Microsc Res Tech 2008; 71:371-9. [PMID: 18300288 DOI: 10.1002/jemt.20565] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Matrix metalloproteinases are zinc dependent endopeptidases belonging to the M10 family of the metalloproteinase superfamily. They are ubiquitous enzymes, structurally and functionally related, with a high degree of sequence homology. They are primarily involved in extracellular matrix (ECM) turn-over and cell migration through their expanding repertoire of substrate affinities. Twenty three different forms of human MMPs have been described to be arranged in eight distinct structural classes. Their interactions with tissue inhibitors of metalloproteinases (TIMPs), and other indigenous inhibitors have been well documented. This manuscript reviews pertinent information available on matrix metalloproteinases and TIMPs in the literature. Light chain-mediated glomerular injury represents an excellent example of how metalloproteinases participate in altering mesangial homeostasis. Investigations regarding these conditions have shown that the physico-chemical characteristics of the light chains govern the pattern of renal damage that will ensue with the mesangium representing the critical site where pathological alterations are centered. The mesangium is either replaced or expanded depending on the light chains involved in the pathologic process.
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Affiliation(s)
- John Keeling
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
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Oneda B, Lods N, Lottaz D, Becker-Pauly C, Stöcker W, Pippin J, Huguenin M, Ambort D, Marti HP, Sterchi EE. Metalloprotease meprin beta in rat kidney: glomerular localization and differential expression in glomerulonephritis. PLoS One 2008; 3:e2278. [PMID: 18509531 PMCID: PMC2386549 DOI: 10.1371/journal.pone.0002278] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2008] [Accepted: 04/17/2008] [Indexed: 01/06/2023] Open
Abstract
Meprin (EC 3.4.24.18) is an oligomeric metalloendopeptidase found in microvillar membranes of kidney proximal tubular epithelial cells. Here, we present the first report on the expression of meprin beta in rat glomerular epithelial cells and suggest a potential involvement in experimental glomerular disease. We detected meprin beta in glomeruli of immunostained rat kidney sections on the protein level and by quantitative RT-PCR of laser-capture microdissected glomeruli on the mRNA level. Using immuno-gold staining we identified the membrane of podocyte foot processes as the main site of meprin beta expression. The glomerular meprin beta expression pattern was altered in anti-Thy 1.1 and passive Heymann nephritis (PHN). In addition, the meprin beta staining pattern in the latter was reminiscent of immunostaining with the sheep anti-Fx1A antiserum, commonly used in PHN induction. Using Western blot and immunoprecipitation assays we demonstrated that meprin beta is recognized by Fx1A antiserum and may therefore represent an auto-antigen in PHN. In anti-Thy 1.1 glomerulonephritis we observed a striking redistribution of meprin beta in tubular epithelial cells from the apical to the basolateral side and the cytosol. This might point to an involvement of meprin beta in this form of glomerulonephritis.
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Affiliation(s)
- Beatrice Oneda
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - Nadège Lods
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - Daniel Lottaz
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | | | - Walter Stöcker
- Institute of Zoology, Johannes Gutenberg University, Mainz, Germany
| | - Jeffrey Pippin
- Division of Nephrology, University of Washington, Seattle, Washington, United States of America
| | - Maya Huguenin
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - Daniel Ambort
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
| | - Hans-Peter Marti
- Division of Nephrology/Hypertension, Inselspital, University of Bern, Bern, Switzerland
| | - Erwin E. Sterchi
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
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Sanders JSF, Huitema MG, Hanemaaijer R, van Goor H, Kallenberg CGM, Stegeman CA. Urinary matrix metalloproteinases reflect renal damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis. Am J Physiol Renal Physiol 2007; 293:F1927-34. [PMID: 17898039 DOI: 10.1152/ajprenal.00310.2007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Renal expression of MMP-2, -9, and tissue inhibitor of MMP-1 (TIMP-1) correlates with histological disease activity in anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV). We studied whether urinary and plasma levels of MMP-2, -9, and TIMP-1 reflect renal expression of these proteins and renal disease-activity in AAV. Urine and plasma samples of patients with AAV who underwent a renal biopsy were collected (n = 32). Urinary activity of MMP-2 and -9 was measured by activity assays. Urinary and plasma levels of MMP-2, MMP-9, and TIMP-1 proteins were measured by ELISA. Healthy controls provided plasma and urine for comparison (n = 31). In patients, the relationship of urinary and plasma levels with renal expression of MMP-2 and MMP-9 and clinical and histological disease activity was studied. Renal MMP expression was compared between patients and controls (n = 8). Urinary MMP-2 and MMP-9 activity and urinary and plasma TIMP-1 levels were significantly higher in patients than in controls. In glomeruli of patients, both MMP-2 and MMP-9 expression reflected active glomerular inflammation. Urinary activity of MMP-2 and MMP-9 did not correlate with renal MMP expression or plasma levels. Urinary MMP activity correlated negatively with glomerular inflammation, but positively with fibrous crescents. Urinary MMP-2 and TIMP-1 levels showed a positive correlation with tubulointerstitial damage and a negative correlation with creatinine clearance. Urinary MMP-2, MMP-9, and TIMP-1 are elevated in AAV but do not reflect renal MMP expression and glomerular inflammation. However, urinary MMP-2 activity and TIMP-1 levels reflect tubulointerstitial damage and correlate negatively with creatinine clearance at biopsy.
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Affiliation(s)
- Jan-Stephan F Sanders
- Univ. Medical Center Groningen, Dept. of Clinical Immunology, Hanzeplein 1, 9700 GZ Groningen, The Netherlands.
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Jansen PL, Rosch R, Jansen M, Binnebösel M, Junge K, Alfonso-Jaume A, Klinge U, Lovett DH, Mertens PR. Regulation of MMP-2 Gene Transcription in Dermal Wounds. J Invest Dermatol 2007; 127:1762-7. [PMID: 17344928 DOI: 10.1038/sj.jid.5700765] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Matrix metalloproteinase-2 (MMP-2, gelatinase A) plays an essential role in angiogenesis, inflammation, and fibrosis. These processes are critical for wound healing and accordingly elevated levels of MMP-2 expression have been detected after skin injury. Our goal was to investigate the transcriptional activation of the MMP-2 gene in a model of skin injury by using two different MMP-2/LacZ-reporter mice. Upon skin injury MMP-2 expression was upregulated, whereas tissue from normal skin stained negative except for occasional macrophages, sweat glands, and hair follicles. Skin injury also activated MMP-2 proteolytic activity and reporter gene expression. We demonstrate that MMP-2 regulatory sequences -1686/+423 drive appropriate injury-induced MMP-2-promoter activation. Reporter gene expression was predominantly detectable in endothelial cells and in macrophages. Deletion of the 5' responsive element, denoted RE-1, residing at -1241/+423 bp of the regulatory sequence led to abrogated MMP-2 transcription in vivo. The findings define a crucial role for the enhancer element RE-1 in injury-induced MMP-2 transcription of the skin.
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Affiliation(s)
- Petra Lynen Jansen
- Interdisciplinary Centre for Clinical Research BIOMAT, University Hospital, RWTH Aachen, Aachen, Germany.
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Gianella A, Nobili E, Abbate M, Zoja C, Gelosa P, Mussoni L, Bellosta S, Canavesi M, Rottoli D, Guerrini U, Brioschi M, Banfi C, Tremoli E, Remuzzi G, Sironi L. Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:1165-77. [PMID: 17392157 PMCID: PMC1829451 DOI: 10.2353/ajpath.2007.060882] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.
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Affiliation(s)
- Anita Gianella
- Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy.
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Mosig RA, Dowling O, DiFeo A, Ramirez MCM, Parker IC, Abe E, Diouri J, Aqeel AA, Wylie JD, Oblander SA, Madri J, Bianco P, Apte SS, Zaidi M, Doty SB, Majeska RJ, Schaffler MB, Martignetti JA. Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Hum Mol Genet 2007; 16:1113-23. [PMID: 17400654 PMCID: PMC2576517 DOI: 10.1093/hmg/ddm060] [Citation(s) in RCA: 158] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The 'vanishing bone' or inherited osteolysis/arthritis syndromes represent a heterogeneous group of skeletal disorders characterized by mineralization defects of affected bones and joints. Differing in anatomical distribution, severity and associated syndromic features, gene identification in each 'vanishing bone' disorder should provide unique insights into genetic/molecular pathways contributing to the overall control of skeletal growth and development. We previously described and then demonstrated that the novel autosomal recessive osteolysis/arthritis syndrome, multicentric osteolysis with arthritis (MOA) (MIM #605156), was caused by inactivating mutations in the MMP2 gene [Al Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R.J., Desnick, R.J. and Martignetti, J.A. (2000) Inherited multicentric osteolysis with arthritis: A variant resembling Torg syndrome in a Saudi family. Am. J. Med. Genet., 93, 11-18.]. These in vivo results were counterintuitive and unexpected since previous in vitro studies suggested that MMP-2 overexpression and increased activity, not deficiency, would result in the bone and joint features of MOA. The apparent lack of a murine model [Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T. and Itohara, S. (1997) Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem., 272, 22389-22392.] has hindered studies on disease pathogenesis and, more fundamentally, in addressing the paradox of how functional loss of a single proteolytic enzyme results in an apparent increase in bone loss. Here, we report that Mmp2-/- mice display attenuated features of human MOA including progressive loss of bone mineral density, articular cartilage destruction and abnormal long bone and craniofacial development. Moreover, these changes are associated with markedly and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2-/- mice have approximately 50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life but these differences have nearly resolved by 4 weeks of age. In addition, despite normal cell numbers in vivo at 8 weeks of life, Mmp2-/- bone marrow cells are unable to effectively support osteoblast and osteoclast growth and differentiation in culture. Targeted inhibition of MMP-2 using siRNA in human SaOS2 and murine MC3T3 osteoblast cell lines resulted in decreased cell proliferation rates. Taken together, our findings suggest that MMP-2 plays a direct role in early skeletal development and bone cell growth and proliferation. Thus, Mmp2-/- mice provide a valuable biological resource for studying the pathophysiological mechanisms underlying the human disease and defining the in vivo physiological role of MMP-2.
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Affiliation(s)
- Rebecca A. Mosig
- Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Oonagh Dowling
- Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Analisa DiFeo
- Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
| | | | - Ian C. Parker
- Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Etsuko Abe
- Department of Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Janane Diouri
- Mineralized Tissue Laboratory, Hospital for Special Surgery, New York, NY 10021, USA
| | - Aida Al Aqeel
- Riyadh Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia
| | - James D. Wylie
- Department of Biomedical Engineering and Orthopedic Research Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Samantha A. Oblander
- Department of Biomedical Engineering and Orthopedic Research Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Joseph Madri
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA
| | - Paolo Bianco
- Department of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy
| | - Suneel S. Apte
- Department of Biomedical Engineering and Orthopedic Research Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Mone Zaidi
- Department of Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Stephen B. Doty
- Mineralized Tissue Laboratory, Hospital for Special Surgery, New York, NY 10021, USA
| | - Robert J. Majeska
- Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Mitchell B. Schaffler
- Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - John A. Martignetti
- Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Orthopedics, Mount Sinai School of Medicine, New York, NY 10029, USA
- Corresponding author: John A. Martignetti, M.D., Ph.D., Mount Sinai School of Medicine, 1425 Madison Ave, Box 1498, New York, NY 10029, , Tel: (212) 659-6744, Fax: (212) 849-2638
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Jansen PL, Kever M, Rosch R, Krott E, Jansen M, Alfonso-Jaume A, Dooley S, Klinge U, Lovett DH, Mertens PR. Polymeric meshes induce zonal regulation of matrix metalloproteinase‐2 gene expression by macrophages and fibroblasts. FASEB J 2007; 21:1047-57. [PMID: 17215487 DOI: 10.1096/fj.06-6755com] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Matrix metalloproteinase-2 (MMP-2) is a key regulator in wound healing that orchestrates tissue remodeling. In the present study the spatial and temporal distribution of MMP-2 gene transcription, protein synthesis, and enzymatic activity were analyzed following polymeric mesh (polyglactin, polypropylene) implantation in transgenic reporter mice harboring MMP-2 regulatory sequences -1686/+423 or -1241/+423. Polymers induced MMP-2 promoter activity in macrophages within the foreign body granuloma via sequences -1686/+423 with concomitantly up-regulated protein synthesis and enzymatic activity. Macrophages distant from mesh filaments exhibited low MMP-2 expression levels. Fibroblasts surrounding mesh material displayed strong MMP-2 gene transcription independent of the included promoter sequences, whereas fibroblasts without close contact to mesh material had low MMP-2 synthesis rates due to silencing activity of sequences -1686/-1241. In vitro studies support a cellular crosstalk concept, as macrophages trans-repressed MMP-2 gene transcription in fibroblasts. The zonal and cell-specific regulation of MMP-2 gene transcription illuminates an intimate cellular crosstalk in foreign body reaction that may provide a new approach for mesh modification.
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Affiliation(s)
- Petra Lynen Jansen
- Interdisciplinary Center for Clinical Research BIOMAT, University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany.
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Zhou X, Jamil A, Nash A, Chan J, Trim N, Iredale JP, Benyon RC. Impaired proteolysis of collagen I inhibits proliferation of hepatic stellate cells: implications for regulation of liver fibrosis. J Biol Chem 2006; 281:39757-65. [PMID: 17060319 DOI: 10.1074/jbc.m605621200] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Myofibroblastic-activated hepatic stellate cells are the major source of the collagen I-rich extracellular matrix in liver fibrosis but also produce matrix metalloproteinases, which remodel this protein. We have investigated the role of collagen I proteolysis in both regulating proliferation and maintaining the activated myofibroblastic phenotype of stellate cells in vitro. Compared with stellate cells plated on normal collagen I, those plated on a collagenase-resistant form of collagen I (r/r collagen) had reduced thymidine incorporation and proliferating cell nuclear antigen expression but increased p21 expression. Collagen I was shown to be rendered resistant to matrix metalloproteinases by artificial cross-linking in vitro using tissue transglutaminase exerted similar antiproliferative effects on stellate cells to r/r collagen. Of the stellate cell activation markers examined (tissue inhibitor of metalloproteinases-1, alpha-smooth muscle actin, matrix metalloproteinases-2 and -9, and procollagen I) only the last was decreased by culture on r/r collagen relative to normal collagen I. Antagonists of integrin alphavbeta3, an integrin reported to stimulate stellate cell proliferation, significantly inhibited adhesion, proliferation, and procollagen I synthesis of stellate cells plated on normal collagen I but had reduced effectiveness on these parameters in cells on r/r collagen. We conclude that proliferation of stellate cells is promoted by pericellular collagen I proteolysis acting via alphavbeta3 integrin. Cross-linking of collagen I by tissue transglutaminase, a process known to occur in chronic liver fibrosis, might not only increase its resistance to matrix metalloproteinases thereby inhibiting resolution of fibrosis but also functions to constrain the fibroproliferative process.
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Affiliation(s)
- Xiaoying Zhou
- Liver Group, University Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton, Hants, SO16 6YD, United Kingdom
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Cantarella G, Risuglia N, Dell'eva R, Lempereur L, Albini A, Pennisi G, Scoto GM, Noonan DN, Bernardini R. TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells. Br J Cancer 2006; 94:1428-35. [PMID: 16622457 PMCID: PMC2361261 DOI: 10.1038/sj.bjc.6603092] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.
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Affiliation(s)
- G Cantarella
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
| | - N Risuglia
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
| | - R Dell'eva
- Laboratory of Experimental Oncology, National Cancer Research Institute, Genova 16100, Italy
| | - L Lempereur
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
| | - A Albini
- Laboratory of Experimental Oncology, National Cancer Research Institute, Genova 16100, Italy
| | - G Pennisi
- Department of Chemical Sciences, University of Catania, Catania 95125, Italy
| | - G M Scoto
- Department of Pharmaceutical Sciences, University of Catania, Catania 95125, Italy
| | - D N Noonan
- Laboratory of Experimental Oncology, National Cancer Research Institute, Genova 16100, Italy
| | - R Bernardini
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy. E-mail:
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Lakhe-Reddy S, Khan S, Konieczkowski M, Jarad G, Wu KL, Reichardt LF, Takai Y, Bruggeman LA, Wang B, Sedor JR, Schelling JR. Beta8 integrin binds Rho GDP dissociation inhibitor-1 and activates Rac1 to inhibit mesangial cell myofibroblast differentiation. J Biol Chem 2006; 281:19688-99. [PMID: 16690620 PMCID: PMC2711893 DOI: 10.1074/jbc.m601110200] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Alpha(v)beta8 integrin expression is restricted primarily to kidney, brain, and placenta. Targeted alpha(v) or beta8 deletion is embryonic lethal due to defective placenta and brain angiogenesis, precluding investigation of kidney alpha(v)beta8 function. We find that kidney beta8 is localized to glomerular mesangial cells, and expression is decreased in mouse models of glomerulosclerosis, suggesting that beta8 regulates normal mesangial cell differentiation. To interrogate beta8 signaling pathways, yeast two-hybrid and co-precipitation studies demonstrated beta8 interaction with Rho guanine nucleotide dissociation inhibitor-1 (GDI). Selective beta8 stimulation enhanced beta8-GDI interaction as well as Rac1 (but not RhoA) activation and lamellipodia formation. Mesangial cells from itgb8-/- mice backcrossed to a genetic background that permitted survival, or gdi-/- mice, which develop glomerulosclerosis, demonstrated RhoA (but not Rac1) activity and alpha-smooth muscle actin assembly, which characterizes mesangial cell myofibroblast transformation in renal disease. To determine whether Rac1 directly modulates RhoA-associated myofibroblast differentiation, mesangial cells were transduced with inhibitory Rac peptide fused to human immunodeficiency virus-Tat, resulting in enhanced alpha-smooth muscle actin organization. We conclude that the beta8 cytosolic tail in mesangial cells organizes a signaling complex that culminates in Rac1 activation to mediate wild-type differentiation, whereas decreased beta8 activation shifts mesangial cells toward a RhoA-dependent myofibroblast phenotype.
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Affiliation(s)
- Sujata Lakhe-Reddy
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - Shenaz Khan
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - Martha Konieczkowski
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - George Jarad
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - Karen L. Wu
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - Louis F. Reichardt
- Departments of Physiology and Biochemistry/Biophysics, University of California, San Francisco and Howard Hughes Medical Institute, San Francisco, California 94143
| | - Yoshimi Takai
- Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine, Osaka 565−0871, Japan
| | - Leslie A. Bruggeman
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - Bingcheng Wang
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
- Department of Pharmacology, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - John R. Sedor
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
- Departments of Physiology and Biophysics, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
| | - Jeffrey R. Schelling
- Department of Medicine, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109
- To whom correspondence should be addressed: MetroHealth Medical Center, 2500 MetroHealth Dr., R415, Cleveland, OH. 44109−1998. Tel.: 216−778−4993; E-mail:
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Rosch R, Lynen-Jansen P, Junge K, Knops M, Klosterhalfen B, Klinge U, Mertens PR, Schumpelick V. Biomaterial-dependent MMP-2 expression in fibroblasts from patients with recurrent incisional hernias. Hernia 2006; 10:125-30. [PMID: 16404489 DOI: 10.1007/s10029-005-0060-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2005] [Accepted: 11/30/2005] [Indexed: 10/25/2022]
Abstract
With regard to the pathogenesis of recurrent incisional hernia, an impaired connective tissue quality leading to an aberrant scarring process has been proposed. For the matrix metalloproteinase (MMP-2) a pathogenetic involvement in direct inguinal hernia development is reported. With mesh implantation as the gold standard treatment for incisional hernias, the aim of the present study was to investigate the MMP-2 expression in patients with recurrent incisional hernias with and without mesh-materials. In primary fibroblast cultures obtained from skin scars in patients with and without recurrent incisional hernias, MMP-2 synthesis and gene expression were investigated. Furthermore, MMP-2 synthesis and gene expression of fibroblasts were compared after incubation with two different mesh materials: polypropylene and absorbable polyglactin filaments. MMP-2 enzyme activity was determined by semiquantitative zymography and mRNA synthesis by quantitative RT-PCR. Both MMP-2 enzyme activity and mRNA expression were similar in hernia and control fibroblasts in vitro. In control fibroblasts mesh incubation did not significantly affect MMP-2 expression, whereas polypropylene mesh contact of fibroblasts from patients with recurrent incisional hernias led to a major decrease of MMP-2 activity and of mRNA expression. In the absence of biomaterials fibroblasts from recurrent incisional hernia, patients have no alterations of their MMP-2 synthesis compared to control fibroblasts, whereas a specific response was found after biomaterial contact hereby indicating differences in fibroblast phenotype.
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Affiliation(s)
- R Rosch
- Department of Surgery, University Hospital Aachen, Aachen, Germany.
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