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Abdollahzadeh F, Khoshdel-Rad N, Moghadasali R. Kidney development and function: ECM cannot be ignored. Differentiation 2022; 124:28-42. [DOI: 10.1016/j.diff.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 01/29/2022] [Accepted: 02/04/2022] [Indexed: 11/03/2022]
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Sobreiro‐Almeida R, Quinteira R, Neves NM. Renal Regeneration: The Role of Extracellular Matrix and Current ECM-Based Tissue Engineered Strategies. Adv Healthc Mater 2021; 10:e2100160. [PMID: 34137210 DOI: 10.1002/adhm.202100160] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/29/2021] [Indexed: 12/15/2022]
Abstract
Natural extracellular matrices (ECM) are currently being studied as an alternative source for organ transplantation or as new solutions to treat kidney injuries, which can evolve to end-stage renal disease, a life devastating condition. This paper provides an overview on the current knowledge in kidney ECM and its usefulness on future investigations. The composition and structure of kidney ECM is herein associated with its intrinsic capacity of remodeling and repair after insult. Moreover, it provides a deeper insight on altered ECM components during disease. The use of decellularized kidney matrices is discussed in the second part of the review, with emphasis on how these matrices contribute to tissue-specific differentiation of embryonic, pluripotent, and other stem cells. The evolution on the field toward different uses of xenogeneic ECM as a biological scaffold material is discussed, namely the major outcomes on whole kidney recellularization and its in vivo implantation. At last, the recent literature on the use of processed kidney decellularized ECM to produce diverse biomaterial substrates, such as hydrogels, membranes, and bioinks are reviewed, with emphasis on future perspectives of its translation into the clinic.
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Affiliation(s)
- Rita Sobreiro‐Almeida
- 3B's Research Group I3Bs–Research Institute on Biomaterials, Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco Guimarães 4805‐017 Portugal
- ICVS/3B's–PT Government Associate Laboratory Braga/Guimarães Portugal
| | - Rita Quinteira
- 3B's Research Group I3Bs–Research Institute on Biomaterials, Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco Guimarães 4805‐017 Portugal
- ICVS/3B's–PT Government Associate Laboratory Braga/Guimarães Portugal
| | - Nuno M. Neves
- 3B's Research Group I3Bs–Research Institute on Biomaterials, Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco Guimarães 4805‐017 Portugal
- ICVS/3B's–PT Government Associate Laboratory Braga/Guimarães Portugal
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Zhou Y, Ma XY, Han JY, Yang M, Lv C, Shao Y, Wang YL, Kang JY, Wang QY. Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop. World J Diabetes 2021; 12:19-46. [PMID: 33520106 PMCID: PMC7807255 DOI: 10.4239/wjd.v12.i1.19] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/05/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is significantly increasing worldwide, and the incidence of its complications is also on the rise. One of the main complications of T2DM is diabetic kidney disease (DKD). The glomerular filtration rate (GFR) and urinary albumin creatinine ratio (UACR) increase in the early stage. As the disease progresses, UACR continue to rise and GFR begins to decline until end-stage renal disease appears. At the same time, DKD will also increase the incidence and mortality of cardiovascular and cerebrovascular diseases. At present, the pathogenesis of DKD is not very clear. Therefore, exploration of the pathogenesis of DKD to find a treatment approach, so as to delay the development of DKD, is essential to improve the prognosis of DKD. AIM To detect the expression of tenascin-C (TNC) in the serum of T2DM patients, observe the content of TNC in the glomerulus of DKD rats, and detect the expression of TNC on inflammatory and fibrotic factors in rat mesangial cells (RMCs) cultured under high glucose condition, in order to explore the specific molecular mechanism of TNC in DKD and bring a new direction for the treatment of DKD. METHODS The expression level of TNC in the serum of diabetic patients was detected by enzyme-linked immunosorbent assay (ELISA), the protein expression level of TNC in the glomerular area of DKD rats was detected by immunohistochemistry, and the expression level of TNC in the rat serum was detected by ELISA. Rat glomerular mesangial cells were cultured. Following high glucose stimulation, the expression levels of related proteins and mRNA were detected by Western blot and polymerase chain reaction, respectively. RESULTS ELISA results revealed an increase in the serum TNC level in patients with T2DM. Increasing UACR and hypertension significantly increased the expression of TNC (P < 0.05). TNC expression was positively correlated with glycosylated haemoglobin (HbA1c) level, body mass index, systolic blood pressure, and UACR (P < 0.05). Immunohistochemical staining showed that TNC expression in the glomeruli of rats with streptozotocin-induced diabetes was significantly increased compared with normal controls (P < 0.05). Compared with normal rats, serum level of TNC in diabetic rats was significantly increased (P < 0.05), which was positively correlated with urea nitrogen and urinary creatinine (P < 0.05). The levels of TNC, Toll-like receptor-4 (TLR4), phosphorylated nuclear factor-κB p65 protein (Ser536) (p-NF-κB p65), and miR-155-5p were increased in RMCs treated with high glucose (P < 0.05). The level of TNC protein peaked 24 h after high glucose stimulation (P < 0.05). After TNC knockdown, the levels of TLR4, p-NF-κB p65, miR-155-5p, connective tissue growth factor (CTGF), and fibronectin (FN) were decreased, revealing that TNC regulated miR-155-5p expression through the TLR4/NF-κB p65 pathway, thereby regulating inflammation (NF-κB p65) and fibrosis (CTGF and FN) in individuals with DKD. In addition, metformin treatment may relive the processes of inflammation and fibrosis in individuals with DKD by reducing the levels of the TNC, p-NF-κB p65, CTGF, and FN proteins. CONCLUSION TNC can promote the occurrence and development of DKD. Interfering with the TNC/TLR4/NF-κB p65/miR-155-5p pathway may become a new target for DKD treatment.
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Affiliation(s)
- Yang Zhou
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Xiao-Yu Ma
- Department of Gerontology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Jin-Yu Han
- Department of Gerontology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Min Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Chuan Lv
- Department of Endocrinology, The People’s Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Ying Shao
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Yi-Li Wang
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Jia-Yi Kang
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
| | - Qiu-Yue Wang
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
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Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease. Kidney Int Rep 2020; 5:1870-1893. [PMID: 33163710 PMCID: PMC7609979 DOI: 10.1016/j.ekir.2020.07.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/06/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023] Open
Abstract
Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain–derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, which include apoptosis, phenotype transformation, and secretion of extracellular matrix components and metalloproteinases. Monoclonal light chains associated with AL-Am but not those producing LCDD are avidly endocytosed by mesangial cells and delivered to the mature lysosomal compartment where amyloid fibrils are formed. Light chains from patients with LCDD exert their pathogenic signaling effect at the cell surface of mesangial cells. These events are generic mesangial responses to a variety of adverse stimuli, and they are similar to those characterizing other more frequent glomerulopathies responsible for many cases of end-stage renal disease. The pathophysiologic events that have been elucidated allow to propose future therapeutic approaches aimed at preventing, stopping, ameliorating, or reversing the adverse effects resulting from the interactions between glomerulopathic light chains and mesangium.
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Herrera GA, Teng J, Zeng C, Xu H, Liang M, Alexander JS, Liu B, Boyer C, Turbat-Herrera EA. Phenotypic plasticity of mesenchymal stem cells is crucial for mesangial repair in a model of immunoglobulin light chain-associated mesangial damage. Ultrastruct Pathol 2018; 42:262-288. [PMID: 29668344 DOI: 10.1080/01913123.2018.1449772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Mesangiopathies produced by glomerulopathic monoclonal immunoglobulin light chains (GLCs) acting on the glomerular mesangium produce two characteristic lesions: AL-amyloidosis (AL-Am) and light chain deposition disease (LCDD). In both cases, the pathology is centered in the mesangium, where initial and progressive damage occurs. In AL-Am the mesangial matrix is destroyed and replaced by amyloid fibrils and in LCDD, the mesangial matrix is increased and remodeled. The collagen IV rich matrix is replaced by tenascin. In both conditions, mesangial cells (MCs) become apoptotic as a direct effect of the GLCs. MCs were incubated in-vitro with GLCs and animal kidneys were perfused ex-vivo via the renal artery with GLCs, producing expected lesions, and then mesenchymal stem cells (MSCs) were added to both platforms. Each of the two platforms provided unique information that when put together created a comprehensive evaluation of the processes involved. A "cocktail" with growth and differentiating factors was used to study its effect on mesangial repair. MSCs displayed remarkable phenotypic plasticity during the repair process. The first role of the MSCs after migrating to the affected areas was to dispose of the amyloid fibrils (in AL-Am), the altered mesangial matrix (in LCDD) and apoptotic MCs/debris. To accomplish this task, MSCs transformed into facultative macrophages acquiring an abundance of lysosomes and endocytotic capabilities required to engage in phagocytic functions. Once the mesangial cleaning was completed, MSCs transformed into functional MCs restoring the mesangium to normal. "Cocktail" made the repair process more efficient.
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Affiliation(s)
- Guillermo A Herrera
- a Departments of Pathology and Translational Pathobiology and Cell Biology and Anatomy , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Jiamin Teng
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Chun Zeng
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Hongzhi Xu
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Man Liang
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - J Steven Alexander
- c Department of Molecular and Cellular Physiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Bing Liu
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Chris Boyer
- c Department of Molecular and Cellular Physiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Elba A Turbat-Herrera
- d Departments of Pathology and Translational Pathobiology , Medicine, and Cell Biology and Anatomy, Louisiana State Health Sciences Center , Shreveport , LA , USA
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Herrera GA, Zeng C, Turbat-Herrera EA, Teng J. Healing the damaged mesangium in nodular glomerulosclerosis using mesenchymal stem cells (MSCs): Expectations and challenges. Ultrastruct Pathol 2017; 40:61-70. [PMID: 27031175 DOI: 10.3109/01913123.2016.1145776] [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: 02/05/2023]
Abstract
It has been shown experimentally that mesenchymal stem cells (MSCs) can be delivered to the mesangium in some conditions such as amyloidosis to clear debris and foreign material, and eventually transform into functional mesangial cells (MCs) and change the altered mesangial areas into normal collagen IV-rich matrix. A more challenging situation is when the matrix is rich in abnormal extracellular matrix proteins, especially those difficult to destroy such as tenascin, and, as a result, assumes a nodular appearance - what is known in pathology jargon as nodular glomerulosclerosis. MSCs find it difficult to dispose of the altered mesangial constituents, an initial step required for mesangial repair to occur successfully. The ability of MSCs to repair damaged mesangium represents a novel therapeutic intervention to reverse mesangial injury and is potentially a powerful and unique approach to prevent progression ending in end-stage renal disease (ESRD). This review will highlight progress that has been made in glomerular, and more specifically mesangial, repair, and will address future expectations and challenges to be confronted as the use of MSCs continues to be explored as a potential application for clinical practice.
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Affiliation(s)
- Guillermo A Herrera
- a Department of Pathology and Translational Pathobiology , Louisiana State University Health Sciences Center , Shreveport , LA , USA.,b Department of Cellular Biology and Anatomy , Louisiana State University Health Sciences Center , Shreveport , LA , USA
| | - Chun Zeng
- a Department of Pathology and Translational Pathobiology , Louisiana State University Health Sciences Center , Shreveport , LA , USA
| | - Elba A Turbat-Herrera
- a Department of Pathology and Translational Pathobiology , Louisiana State University Health Sciences Center , Shreveport , LA , USA.,b Department of Cellular Biology and Anatomy , Louisiana State University Health Sciences Center , Shreveport , LA , USA.,c Department of Medicine, Feist-Weiller Cancer Center , Louisiana State University Health Sciences Center , Shreveport , LA , USA
| | - Jiamin Teng
- a Department of Pathology and Translational Pathobiology , Louisiana State University Health Sciences Center , Shreveport , LA , USA
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Herrera GA, Turbat-Herrera EA, Teng J. Animal Models of Light Chain Deposition Disease Provide a Better Understanding of Nodular Glomerulosclerosis. Nephron Clin Pract 2016; 132:119-36. [PMID: 26794829 DOI: 10.1159/000443282] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 12/06/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Light chain deposition disease (LCDD) is a model of glomerulosclerosis. The mature lesion of LCDD mimics nodular glomerulosclerosis in diabetic nephropathy. The pathogenetic mechanisms involved are similar in both disorders, though the causative factors are entirely different. This fact highlights the generic response of the mesangium to varied stimuli. In-vitro work has provided much insight into the pathogenesis of glomerulosclerosis in LCDD where the mesangium is the main target for initiation and progression of the disease. The lack of animal models has prevented the development of further therapeutic approaches to be tested in platforms such as ex-vivo and in-vivo preparing the way for human studies. METHODS Light chains (LCs) obtained from the urine of patients with renal biopsy proven LCDD were delivered to glomeruli using ex-vivo and in-vivo approaches to address whether in-vitro information could be validated in-vivo. Selected in-vitro studies were conducted to address specific issues dealing with mesangial cell (MC) differentiation and composition of extracellular matrix to add additional data to the existing vast literature. Using light, electron and scanning microscopy together with immunohistochemistry and ultrastructural immunolabeling, MCs incubated in Matrigel with LCDD LCs, as well as delivery of such LCs by perfusion via renal artery (ex-vivo) and penile dorsal vein (in-vivo) to the kidneys, validation of pathogenetic pathways previously suggested in in-vitro experiments were tested and confirmed. RESULTS The animal models described in this manuscript provide validation for the in-vitro data that have been previously published and expand our appreciation of the important role that caveolin-1 plays in signaling events essential for the downstream sequence of events that eventually leads to the pathological alterations centered in the mesangium characterized by an increase in matrix production and formation of mesangial nodules. CONCLUSIONS The same findings observed in renal biopsies of patients with LCDD (mesangial expansion with increased matrix) were documented in the ex-vivo and in-vivo platforms. In-vivo understanding of the pathogenesis of mesangial glomerulosclerosis, as accomplished in the reported research, is crucial for the design of novel therapeutic approaches to treat a number of glomerulopathies with similar pathogenetic mechanisms. Inhibiting interactions between glomerulopathic LCs and MCs or interrupting the protein production/secretion pathways are potentially effective therapeutic maneuvers. The results obtained with caveolin-1 knockout mice emphasized the importance of caveolin-1 in signaling events essential to effect downstream mesangial alterations.
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Affiliation(s)
- Guillermo A Herrera
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, La., USA
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Závada J, Uher M, Svobodová R, Olejárová M, Hušáková M, Ciferská H, Hulejová H, Tomčík M, Šenolt L, Vencovský J. Serum tenascin-C discriminates patients with active SLE from inactive patients and healthy controls and predicts the need to escalate immunosuppressive therapy: a cohort study. Arthritis Res Ther 2015; 17:341. [PMID: 26608564 PMCID: PMC4660660 DOI: 10.1186/s13075-015-0862-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 11/13/2015] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION The aim of this study was to examine whether circulating levels of the proinflammatory glycoprotein tenascin-C (TNC) are useful as an activity-specific or predictive biomarker in systemic lupus erythematosus (SLE). METHODS Serum TNC levels were determined by enzyme-linked immunosorbent assay at inception visit in a prospective cohort of 59 SLE patients, and in 65 healthy controls (HC). SLE patients were followed for a mean of 11 months, disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) and British Isles Lupus Assessment Group disease activity index (BILAG-2004), clinical and laboratory data were recorded every 3-6 months, and changes in glucocorticoids (GC) and immunosuppressants (IS) were recorded serially. We examined cross-sectionally the relationships between serum concentrations of TNC and SLE status, SLEDAI-2 K scores, strata of disease activity, and levels of conventional biomarkers [anti-double-stranded DNA (dsDNA), anti-nucleosome antibodies, C3 and C4]. We also explored the utility of TNC levels for predicting disease flares, defined as (i) new/increased GC, (ii) new/increased GC or IS, and (iii) increase in SLEDAI by ≥3 or (iv) BILAG A or B flare. RESULTS There was no significant difference in the mean levels of TNC between the SLE patients and HC. However, in SLE patients with active disease (SLEDAI ≥6), the TNC levels were significantly higher than in the HC (p = 0.004) or in patients with no/low disease activity (p = 0.004). In SLE patients, TNC levels were significantly associated with positivity of anti-dsDNA (p = 0.03) and anti-nucleosome antibodies (p = 0.008). Flares defined by a need to escalate immunosuppressive therapy were captured more frequently and earlier than flares defined by standard activity indices. Higher baseline levels of serum TNC presented a significantly greater risk of flare (i) [hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.11-1.73] or (ii) (HR 1.25, 95% CI 1.02-1.52) but not of flares (iii) or (iv). The baseline serum TNC level was the single most important independent predictor of flare (i) compared with conventional biomarkers. CONCLUSIONS TNC is not disease-specific, but it seems to indicate the activity of SLE and may predict the need to escalate immunosuppressive therapy. TNC levels may thus serve as a useful activity-specific and predictive biomarker in SLE.
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Affiliation(s)
- Jakub Závada
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Michal Uher
- Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic.
| | - Radka Svobodová
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Marta Olejárová
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Markéta Hušáková
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Hana Ciferská
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Hana Hulejová
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Michal Tomčík
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Ladislav Šenolt
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
| | - Jiří Vencovský
- Institute of Rheumatology, Prague, and Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Praha 2, 12850, Prague, Czech Republic.
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Transcriptome analysis of renal ischemia/reperfusion injury and its modulation by ischemic pre-conditioning or hemin treatment. PLoS One 2012; 7:e49569. [PMID: 23166714 PMCID: PMC3498198 DOI: 10.1371/journal.pone.0049569] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 10/10/2012] [Indexed: 01/06/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) is a leading cause of acute renal failure. The definition of the molecular mechanisms involved in renal IRI and counter protection promoted by ischemic pre-conditioning (IPC) or Hemin treatment is an important milestone that needs to be accomplished in this research area. We examined, through an oligonucleotide microarray protocol, the renal differential transcriptome profiles of mice submitted to IRI, IPC and Hemin treatment. After identifying the profiles of differentially expressed genes observed for each comparison, we carried out functional enrichment analysis to reveal transcripts putatively involved in potential relevant biological processes and signaling pathways. The most relevant processes found in these comparisons were stress, apoptosis, cell differentiation, angiogenesis, focal adhesion, ECM-receptor interaction, ion transport, angiogenesis, mitosis and cell cycle, inflammatory response, olfactory transduction and regulation of actin cytoskeleton. In addition, the most important overrepresented pathways were MAPK, ErbB, JAK/STAT, Toll and Nod like receptors, Angiotensin II, Arachidonic acid metabolism, Wnt and coagulation cascade. Also, new insights were gained about the underlying protection mechanisms against renal IRI promoted by IPC and Hemin treatment. Venn diagram analysis allowed us to uncover common and exclusively differentially expressed genes between these two protective maneuvers, underscoring potential common and exclusive biological functions regulated in each case. In summary, IPC exclusively regulated the expression of genes belonging to stress, protein modification and apoptosis, highlighting the role of IPC in controlling exacerbated stress response. Treatment with the Hmox1 inducer Hemin, in turn, exclusively regulated the expression of genes associated with cell differentiation, metabolic pathways, cell cycle, mitosis, development, regulation of actin cytoskeleton and arachidonic acid metabolism, suggesting a pleiotropic effect for Hemin. These findings improve the biological understanding of how the kidney behaves after IRI. They also illustrate some possible underlying molecular mechanisms involved in kidney protection observed with IPC or Hemin treatment maneuvers.
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Basnayake K, Stringer SJ, Hutchison CA, Cockwell P. The biology of immunoglobulin free light chains and kidney injury. Kidney Int 2011; 79:1289-301. [DOI: 10.1038/ki.2011.94] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Herrera GA, Turbat-Herrera EA. Renal diseases with organized deposits: an algorithmic approach to classification and clinicopathologic diagnosis. Arch Pathol Lab Med 2010; 134:512-31. [PMID: 20367304 DOI: 10.5858/134.4.512] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Most renal diseases with organized deposits are relatively uncommon conditions, and proper pathologic characterization determines the specific diagnosis. Different entities with specific clinical correlates have been recognized, and their correct diagnosis has an impact on patient management, treatment options, and determination of prognosis. OBJECTIVE The diagnosis of these conditions depends on careful evaluation of the findings by light microscopy together with immunofluorescence and electron microscopy. The objective of this manuscript is to delineate an algorithmic approach helpful in the pathologic assessment of these conditions at the light microscopic level. In some diseases, the immunomorphologic parameters short of electron microscopy provide solid information to suggest or make a definitive diagnosis. Nevertheless, electron microscopy plays a crucial role, because the criteria to separate these entities often are heavily influenced by the electron microscopic findings. Accepted diagnostic criteria for each of these conditions are discussed. DESIGN Information used for this manuscript is gathered from published data and the authors' experience. RESULTS The most common of these conditions is amyloidosis, which may account for as many as 5% to 8% of all renal biopsies in some renal pathology practices. Fibrillary, immunotactoid, and cryoglobulinemic glomerulopathies together represent, at most, 1% of all renal biopsies performed for medical renal diseases. Diabetic fibrillosis also is uncommon. Glomerulopathies associated with fibronectin deposits and collagenofibrotic glomerulopathy are extremely rare. CONCLUSIONS A systematic, algorithmic approach to the evaluation of the renal biopsies from patients with these disorders is very helpful to rule out certain conditions in the early stages of the evaluation of the biopsies. However, it is not uncommon for the final definitive diagnosis to be reached only after electron microscopic evaluation.
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Affiliation(s)
- Guillermo A Herrera
- Department of Pathology, Nephrocor, Bostwick Laboratories Arizona, Tempe, 85281, USA.
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Guillermo A. Herrera, William J. Ru. Glomerulopathic Light Chain-Mesangial Cell Interactions Modulate in Vitro Extracellular Matrix Remodeling and Reproduce Mesangiopathic Findings Documented in Vivo. Ultrastruct Pathol 2009. [DOI: 10.1080/019131299281752] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Arikan H, Koc M, Cakalagaoglu F, Tuglular S, Ozener C, Akoglu E. Histopathological changes and tumour necrosis factor-alpha, transforming growth factor-beta and tenascin expression in patients with primary type I membranoproliferative glomerulonephritis in remission. Nephrology (Carlton) 2009; 14:219-26. [PMID: 19298642 DOI: 10.1111/j.1440-1797.2008.01048.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM Primary type I membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerular disease with a high relapse rate and poor prognosis. The aim of this study was: (i) to evaluate the histopathological findings associated with remission; and (ii) to document the possible clinical and histopathological factors predicting relapses. METHODS Eleven type I MPGN patients (five men, six women; mean age, 38.8+/-13.5 years) who were in remission for at least 1 year after the cessation of immunosuppressive drugs were re-biopsied. The intensity of immunostaining for tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and tenascin was graded from 0 (no staining) to 3+ (maximum staining). RESULTS Mean baseline mesangial cellularity score and tubulointerstitial infiltration score were reduced and mesangial matrix expansion score was increased at protocol re-biopsies compared to baseline. The glomerular and tubulointerstitial staining scores for TGF-beta1 and tenascin were higher than that of baseline. Reduced tubulointerstitial TNF-alpha expression was found in re-biopsy specimens compared to baseline. Patients have been followed for a mean time of 51.5+/-22.2 months after the protocol biopsy. Eight patients had a relapse. Mesangial cellularity score and glomerular tenascin expression at re-biopsy specimens were higher in relapsed patients compared to those without a relapse. CONCLUSION Our study shows that mesangial cellularity and tubulointerstitial cell infiltration are reducing whereas mesangial matrix expansion, glomerular and tubulointerstitial TGF-beta1 and tenascin expression are increasing with remission. The higher mesangial cell proliferation and glomerular tenascin scores in remission are associated with the development of relapse.
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Affiliation(s)
- Hakki Arikan
- Division of Nephrology, Department of Medicine, Marmara Medical School, Istanbul, Turkey.
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15
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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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16
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Teng J, Turbat-Herrera EA, Herrera GA. Role of translational research advancing the understanding of the pathogenesis of light chain-mediated glomerulopathies. Pathol Int 2007; 57:398-412. [PMID: 17587239 DOI: 10.1111/j.1440-1827.2007.02116.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Glomerulopathic light chains engage in pathological interactions with mesangial cells resulting in alterations in glomerular homeostasis. The crucial pathological events are centered in the mesangium and, therefore, research dealing with pathogenesis of these disorders is focused on this glomerular compartment. Particular physicochemical characteristics of these light chains are responsible for their ability to alter mesangial milieu leading to glomerular damage. An in vitro model has been used to dissect the processes involved. This model has been instrumental in providing a solid platform from which to observe in a dynamic fashion how mesangial cells handle pathogenic light chains and the sequential steps that are involved in the progressive glomerular damage. Key steps amenable to possible modulation have been defined and should provide a solid platform to design and test therapeutic interventions. In the past significant difficulties have been encountered in the development of animal models of light chain-induced glomerular damage. However, in the last few years a new generation of animal models has emerged to address whether what has been documented in vitro retains significance in vivo. Preliminary observations appear to substantiate this.
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Affiliation(s)
- Jiamin Teng
- Department of Pathology, Saint Louis University Medical Center, Sait Louis, Missouri 63104, USA
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Ronco P, Plaisier E, Mougenot B, Aucouturier P. Immunoglobulin Light (Heavy)-Chain Deposition Disease: From Molecular Medicine to Pathophysiology-Driven Therapy. Clin J Am Soc Nephrol 2006; 1:1342-50. [PMID: 17699367 DOI: 10.2215/cjn.01730506] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Light-, light- and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light- and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly kappa, and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.
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Affiliation(s)
- Pierre Ronco
- INSERM UMR S 702, Université Pierre et Marie Curie-Paris 6, Paris, France.
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Keeling J, Herrera GA. Matrix metalloproteinases and mesangial remodeling in light chain-related glomerular damage. Kidney Int 2005; 68:1590-603. [PMID: 16164636 DOI: 10.1111/j.1523-1755.2005.00571.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) belong to the zinc endopeptidase subgroup of the metalloproteinase superfamily and are primarily involved in extracellular matrix (ECM) remodeling. Alterations of the mesangial ECM in AL-amyloidosis (AL-Am) and light chain deposition disease (LCDD) are crucial in their pathogeneses as two divergent entities. METHODS Protein expression patterns of five MMPs (MMP-1, 2, 3, 7, and 9) in renal tissues obtained from autopsies and kidney biopsies, and cultured human mesangial cells (HMCs) treated with light chains obtained from the urines of patients with AL-Am and LCDD were analyzed. MMP mRNA expressions were determined in glomeruli following laser capture microdissection and selective MMP microarray. Zymography was used to assess MMP activity. RESULTS The average glomerular MMP expression was 6 times greater in AL-Am than LCDD and negative control renal tissues with different expression profiles: MMP-1, 7 > 9 > 3 > 2, MMP-1 > 2, 9 > 3 > 7, and MMP-2, 3, 7 > 9 > 1, respectively. Microdissected glomeruli and HMCs treated with light chains expressed higher levels of MMP mRNA and proteins in AL-Am than LCDD. Zymography was used to assess activity demonstrating increased MMP-2 in AL-Am. CONCLUSION Altered expressions of MMPs play a key role in the pathogenesis of AL-Am and LCDD. MMPs were more highly expressed in AL-Am compared to LCDD.
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Affiliation(s)
- John Keeling
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA
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Kobayashi T, Uehara S, Ikeda T, Itadani H, Kotani H. Vitamin D3 up-regulated protein-1 regulates collagen expression in mesangial cells. Kidney Int 2003; 64:1632-42. [PMID: 14531794 DOI: 10.1046/j.1523-1755.2003.00263.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Hyperglycemia is a known risk factor in the pathogenesis of nephropathy, and collagen accumulation due to an increase reactive oxygen species (ROS) has been suspected to be one of the reasons for high glucose-mediated diseases. However, molecular mechanisms that connect glucose stimulation, oxidative stress, and collagen induction are unknown. METHODS We examined global changes in gene expression patterns following high glucose stimulation by using DNA microarray technology in cultured human mesangial cells. The expression of vitamin D3 up-regulated protein-1 (VDUP-1), our candidate for the molecular mediator, was evaluated in the human mesangial cells, mouse mesangial cell line, and kidneys of diabetic mice by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Truncated VDUP-1 proteins were used to test the effects of VDUP-1 on the biosynthesis of collagen in mesangial cells. RESULTS Expression of VDUP-1, which was reported as an inhibitor of thioredoxin, was induced rapidly and constantly after exposure to high concentrations of glucose upon analysis with DNA microarray. Overexpression of VDUP-1 gene in cultured mesangial cells resulted in type IV collagen alpha1 chain (COL4A1) mRNA induction and accumulation of type IV collagen protein. However, induction of COL4A1 expression was abolished with a deletion mutant of VDUP-1, which lost thioredoxin-interacting domain. Also, streptozotocin-induced diabetic mice were shown to overexpress VDUP-1 as well as COL4A1. CONCLUSION VDUP-1 mediates collagen accumulation in mesangial cells and could be the molecular mediator/marker for fibrosis in diabetic nephropathy caused by chronic hyperglycemia such as diabetes.
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Affiliation(s)
- Tsutomu Kobayashi
- Banyu Tsukuba Research Institute and Merck Research Laboratories, Tsukuba, Ibaraki, Japan
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20
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Matsumoto K, Hiraiwa N, Yoshiki A, Ohnishi M, Kusakabe M. Tenascin-C expression and splice variant in habu snake venom-induced glomerulonephritis. Exp Mol Pathol 2002; 72:186-95. [PMID: 12009782 DOI: 10.1006/exmp.2002.2432] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Extracellular matrix glycoprotein tenascin-C (TNC) expression is up-regulated in tissue remodeling processes such as tumorigenesis and wound healing. Mouse tenascin-C contains six alternatively spliced domains (A1, A2, A4, B, C, and D) between the fifth and the sixth type III fibronectin domains, which generate large numbers of TNC isoforms. To study TNC isoform variability of wound healing in mice, we induced glomerulonephritis by using Habu snake venom (HSV) and examined alternatively spliced regions by the reverse transcription polymerase chain reaction (RT-PCR) technique. RT-PCR products were separated into seven bands in both healthy and diseased kidneys. Among the seven bands, those containing one or five alternatively spliced domains were mainly up-regulated from 2 days to 1 week after HSV injection. Southern blotting revealed that only domain-D detected all six bands in both healthy and diseased kidneys. Furthermore, only the domain-C transcriptional level did not show an obvious change in progress following HSV injection. These results suggested that (a) the isoforms containing one or five alternatively spliced domains play important roles in the healing process of glomerulonephritis, (b) domain-D is particularly significant in kidney, and (c) domain-C may not play an important role in the healing process of HSV-induced glomerulonephritis.
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Affiliation(s)
- Kenji Matsumoto
- Experimental Animal Division, Bio Resource Center, RIKEN, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
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Matsumoto K, Hiraiwa N, Yoshiki A, Ohnishi M, Kusakabe M. PDGF receptor-alpha deficiency in glomerular mesangial cells of tenascin-C knockout mice. Biochem Biophys Res Commun 2002; 290:1220-7. [PMID: 11811993 DOI: 10.1006/bbrc.2001.6316] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Tenascin-C (TNC) knockout (TNKO) mice showed reduced proliferation of mesangial cells and abnormal restoration after habu-snake venom (HSV)-induced glomerulonephritis. In this study, we examined the relationship of TNC and platelet-derived growth factor receptor (PDGFR) in glomerular mesangial cells. TNC and PDGFR-alpha and -beta transcriptions were up-regulated in wild type (WT) mice after HSV injection, but in TNKO mice PDGFR-alpha transcription was not up-regulated. Immunohistochemistry showed that PDGFR-alpha was found in mesangial areas of colocalized alpha-smooth muscle actin, but in TNKO mice it was not detectable. In vitro studies showed that the expressions of PDGFR-alpha and -beta mRNA and protein in cultured glomerular mesangial cells (GMC) of TNKO mice were lower than those in WT GMC. These results suggest that failures of both TNC and PDGFR-alpha are a candidate for abnormal restoration of TNKO mice.
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Affiliation(s)
- Kenji Matsumoto
- Experimental Animal Division, Bio Resource Center, RIKEN, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.
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22
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Wagrowska-Danilewicz M, Danilewicz M. Renal interstitial tenascin immunostaining and immune cell infiltration in IgA nephropathy. Nephrology (Carlton) 2001. [DOI: 10.1046/j.1440-1797.2001.00050.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
It has been observed that with Masugi nephritis in Wistar rats the initiation of endocapillary proliferative changes with macrophage accumulation is usually followed by glomerular sclerosis without extracapillary extension. In the present study, the provocation of an extracapillary lesion was attempted using accelerated Masugi nephritis in Wistar-Kyoto rats. In order to accelerate the accumulation of monocyte/macrophages, the administration of methylcellulose was added in an additional group. The development and fate of extracapillary lesions were analyzed histopathologically and immunohistochemically. As a result, the formation of extracapillary proliferation of granulomatous lesions could be initiated in this model. Granulomatous lesions were composed of CD4+ T cells and CD8+ T cells and monocyte/macrophages including multinucleated giant cells. These inflammatory cells had seemingly escaped from the capillary lumen through the injured glomerular basement membrane and formed cellular and granulomatous crescents. In addition, tenascin was strongly expressed in cellular crescents and was a unique extracellular matrix at this cellular stage. The cellular crescents then progressed to sclerosis with the formation of increased collagenous extracellular matrix. These results suggest that a delayed-type hypersensitivity plays a role in granulomatous crescent formation, even though the initial glomerular injury was evoked by a humoral antibody.
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Affiliation(s)
- T Horio
- Department of Pathology, Shinshu University School of Medicine, Matsumoto, Japan.
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Bicknell GR, Williams ST, Shaw JA, Pringle JH, Furness PN, Nicholson ML. Differential effects of cyclosporin and tacrolimus on the expression of fibrosis-associated genes in isolated glomeruli from renal transplants. Br J Surg 2000; 87:1569-75. [PMID: 11091247 DOI: 10.1046/j.1365-2168.2000.01577.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Chronic allograft nephropathy is characterized by an excessive accumulation of extracellular matrix proteins leading to glomerular and interstitial fibrosis. The aim of this study was to determine the effects of two different immunosuppressive agents (cyclosporin and tacrolimus) on the expression of the genes controlling extracellular matrix deposition in renal transplant glomeruli. METHODS Fifty-one renal transplant recipients were randomized to receive immunosuppression with either microemulsion cyclosporin or tacrolimus. Isolated glomeruli were plucked from protocol transplant biopsies performed 1 week, 3 months and 6 months after transplantation. Expression of the genes for collagen IValpha2, collagen III, matrix metalloproteinase 2, tissue inhibitor of metalloproteinases (TIMP) 1 and TIMP-2, tenascin and transforming growth factor (TGF) beta1 was studied by quantitative reverse transcriptase-polymerase chain reaction. RESULTS The expression of messenger RNA (mRNA) for collagen III and TIMP-1 was significantly higher in patients receiving cyclosporin therapy than in those having tacrolimus (P < 0.01); this finding was accounted for by differences in the biopsy material at 1 week. A significant difference in collagen III, TIMP-1 and TIMP-2 mRNA expression was also detected between patients depending on the source of renal donor (cadaveric or living). There were no significant differences in the level of glomerular TGF-beta1. CONCLUSION The data provide new in vivo evidence that tacrolimus may exert a less fibrogenic influence on transplant glomeruli than cyclosporin.
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Affiliation(s)
- G R Bicknell
- Department of Surgery, Leicester General Hospital, UK
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Pugliese G, Pricci F, Romeo G, Leto G, Amadio L, Iacobini C, Di Mario U. Autocrine and paracrine mechanisms in the early stages of diabetic nephropathy. J Endocrinol Invest 1999; 22:708-35. [PMID: 10595837 DOI: 10.1007/bf03343635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- G Pugliese
- Dipartimento di Scienze Cliniche, Endocrinologia III, La Sapienza University, Rome, Italy.
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Wagrowska-Danilewicz M, Danilewicz M. Immunohistochemical study of tenascin in mesangial proliferative (IgA-negative) glomerulonephritis. Acta Histochem 1999; 101:351-9. [PMID: 10443297 DOI: 10.1016/s0065-1281(99)80035-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Glomerular and interstitial expression of tenascin was examined by an indirect immunoperoxidase method in renal biopsy specimens from 27 patients with mesangial proliferative (IgA-negative) glomerulonephritis (MesProGN). Histologically normal samples of kidney tissue (n = 10) obtained from patients with renal trauma were used as controls. In patients with MesProGN, expression of tenascin in glomeruli and interstitium was significantly higher as compared with controls. Tenascin was present in mesangial regions and particularly in areas with interstitial damage. Our results confirm that tenascin is present in normal renal tissue and show a strongly positive correlation between glomerular tenascin expression and surface of mesangial areas and between interstitial expression of tenascin and the relative interstitial cortical volume in patients with MesProGN. In addition, there was a significant correlation between intensity of glomerular and interstitial tenascin staining and serum creatinine levels. Our data indicate that tenascin accumulates in glomeruli and interstitium in patients with MesProGN. Therefore, immunohistochemical staining of tenascin may be a useful marker of progression of the disease in this type of glomerulonephritis.
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Abstract
Tenascin was immunolocalized in the chinchilla cochlea and vestibular system to better understand the functional morphology of the inner ear. Inner ear tissues were fixed with acetone, decalcified and cryosectioned. Indirect immunofluorescence, using antibodies directed against human tenascin epitopes, were used to detect tenascin. As a positive control, tenascin immunoreactivity was found in kidney, cortical mesangial cells and the extracellular matrix of glomeruli and medullary tubule interstitial spaces, concurring with previously reported results. In the cochlea, tenascin immunoreactivity was present in osteocytes, the mesothelial cells underlying the basilar membrane (BM) and within the fibrous matrix of the BM. Greater reactivity was observed in the mesothelial cells than in the fibrous matrix of the BM. In the vestibular system, tenascin immunoreactivity formed a diffuse band directly beneath the basal lamina of the ampullary and otoconial organs. Tenascin immunoreactivity was also observed in cup-shaped regions between the type I vestibular hair cells and their surrounding VIII nerve calyces in the ampullary and otoconial organs. This is the first report of the anatomical distribution of tenascin in the adult, mammalian inner ear, other than our previously published abstract P.A. Santi and D. Swartz, Soc. Neurosci. Abstr. 23 (1997) 731.
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Affiliation(s)
- D J Swartz
- University of Iowa Medical School, Iowa City 52242, USA
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Sasaki S, Bao Q, Hughes RC. Galectin-3 modulates rat mesangial cell proliferation and matrix synthesis during experimental glomerulonephritis induced by anti-Thy1.1 antibodies. J Pathol 1999; 187:481-9. [PMID: 10398110 DOI: 10.1002/(sici)1096-9896(199903)187:4<481::aid-path263>3.0.co;2-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Galectin-3 is a beta-galactoside-binding protein synthesized by macrophages and other inflammatory cells and expressed in various branching epithelia, including the developing kidney. The expression of galectin-3 has been studied in a rat model of acute mesangial proliferative glomerulonephritis in which a single injection of anti-Thy1.1 antibodies leads to destruction of mesangial cells expressing a Thy1.1 epitope on their surface. The glomerular lesion is characterized by expansion of the mesangial matrix, especially laminin and collagen type IV, and mesangial hypercellularity. Galectin-3 expression, which is sparse in mature rat kidney and confined to the apical face of some distal tubules, is increased within 1-3 days following antibody administration, with the recruitment of glomerular macrophages and pronounced neo-expression in the cytoplasm and at the basal face of distal tubules. At later times, galectin-3 is detected immunohistochemically in the repopulating mesangial cell mass, preceding the extensive mesangial deposition of laminin and collagen type IV. Mesangial cells in culture do not produce appreciable amounts of galectin-3 but do bind and endocytose exogenously added lectin. Addition of galectin-3 to primary cultures of mesangial cells prepared from normal rats induces a 1.5-fold increase in the synthesis of collagen type IV and it also acts in synergy with a quantitatively similar stimulatory effect of transforming growth factor beta (TGF-beta) on matrix synthesis. Exogenous galectin-3 prolongs the survival of mesangial cells in serum-free cultures and also protects these cells against cytotoxic effects of TGF-beta. The data support the notion that the increased expression and secretion of galectin-3 in infiltrating macrophages and in distal tubular epithelia, together with up-regulation of IL-1beta and TGF-beta genes, play a role in mesangial hypercellularity in the progression of one model of inflammatory renal disease.
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Affiliation(s)
- S Sasaki
- National Institute for Medical Research, Mill Hill, London, UK
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29
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Shigematsu H, Yamaguchi N, Koyama A. Glomerulointerstitial events in rapidly progressive nephritic syndrome, with special reference to histologic grade and stage on the renal lesions. Clin Exp Nephrol 1998. [DOI: 10.1007/bf02480462] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Masaki T, Yorioka N, Taniguchi Y, Ogawa T, Naito T, Nishiki T, Harada Y, Yamakido M. Role of tenascin in human immunoglobulin A nephropathy. J Int Med Res 1997; 25:247-254. [PMID: 9364287 DOI: 10.1177/030006059702500502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Tenascin is a component of the extracellular matrix that responds rapidly to inflammation or injury. The activity index and chronicity index of immunoglobulin A nephropathy are mainly used to decide whether or not steroid therapy is indicated, but are sometimes difficult to evaluate histologically. We investigated whether tenascin staining of the glomeruli was an indicator of the activity or chronicity indices in patients with immunoglobulin A nephropathy. Tenascin staining was evaluated immunohistochemically in 38 renal specimens, including 32 from patients with immunoglobulin A nephropathy and six from control kidneys, and the extent of staining was scored. Tenascin staining was correlated with the chronicity index (r = 0.643, P < 0.0003) but not with the activity index.
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Affiliation(s)
- T Masaki
- Second Department of Internal Medicine, Hiroshima University School of Medicine, Japan
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31
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Miner JH, Sanes JR. Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol 1996; 135:1403-13. [PMID: 8947561 PMCID: PMC2121079 DOI: 10.1083/jcb.135.5.1403] [Citation(s) in RCA: 219] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Collagen IV is a major structural component of all basal laminae (BLs). Six collagen IV alpha chains are present in mammals; alpha 1 and alpha 2(IV) are broadly expressed in embryos and adults, whereas alpha 3-6(IV) are restricted to a defined subset of BLs. In the glomerular BL of the kidney, the alpha 1 and alpha 2(IV) chains are replaced by the alpha 3-5(IV) chains as development proceeds. In humans, mutation of the collagen alpha 3, alpha 4, or alpha 5(IV) chain genes results in a delayed onset renal disease called Alport syndrome. We show here that mice lacking collagen alpha 3(IV) display a renal phenotype strikingly similar to Alport syndrome: decreased glomerular filtration (leading to uremia), compromised glomerular integrity (leading to proteinuria), structural changes in glomerular BL, and glomerulonephritis. Interestingly, numerous changes in the molecular composition of glomerular BL precede the onset of renal dysfunction; these include loss of collagens alpha 4 and alpha 5(IV), retention of collagen alpha 1/2(IV), appearance of fibronectin and collagen VI, and increased levels of perlecan. We suggest that these alterations contribute, along with loss of collagen IV isoforms per se, to renal pathology.
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Affiliation(s)
- J H Miner
- Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Rupprecht HD, Schöcklmann HO, Sterzel RB. Cell-matrix interactions in the glomerular mesangium. Kidney Int 1996; 49:1575-82. [PMID: 8743458 DOI: 10.1038/ki.1996.228] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown to modulate cell behavior, including cellular responses to soluble regulator molecules. In addition to the long-recognized role of such interactions in cell localization, anchoring and differentiation during embryogenesis, they are also involved in diverse processes such as maintenance of tissue integrity, response of cells to mechanical stress, inflammatory response, wound healing, tumor cell growth and metastasis as well as apoptosis. Over the last several years, evidence has been reported that extensive "cross-talk" between glomerular mesangial cells (MCs), ECM molecules and soluble mediator substances also affects the proliferative and synthetic phenotype of MCs. This is likely to be relevant for the behavior of MCs during embryonic development, tissue repair and disease processes of glomeruli. The potential biologic and clinical relevance of cell-matrix interactions in the glomerulus makes their elucidation a challenging goal in current kidney research. In this brief review, we present selected aspects of recent investigations concerning the mesangial matrix and its interactions with MCs. In addition to results from cell culture studies, descriptive findings on abnormalities of the ECM and their potential role for the altered MC behavior in glomerular disease will also be discussed.
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Affiliation(s)
- H D Rupprecht
- Medizinische Klinik IV, Universität Erlangen-Nürnberg, Germany
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Affiliation(s)
- P N Furness
- Department of Pathology, Leicester General Hospital
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Shiiki H, Nishino T, Uyama H, Kimura T, Nishimoto K, Hashimoto T, Fujii Y, Dohi K. Alterations in extracellular matrix components and integrins in patients with preeclamptic nephropathy. Virchows Arch 1996; 427:567-73. [PMID: 8605567 DOI: 10.1007/bf00202887] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The glomerular features of patients with preeclampsia consist of swelling of endothelial cells, subendothelial deposits of incompletely defined material, and thickening of the capillary walls. These abnormalities are thought to resolve in the postpartum period. The distribution of extracellular matrix (ECM) components and integrins was investigated in 10 such patients. Frozen sections and paraffin-embedded sections were stained with antibodies to type IV collagen, laminin (LN), fibronectin (FN), vitronectin (VN), tenascin (TN), fibronectin receptor (FNR), and vitronectin receptor (VNR). In preeclamptic nephropathy, the accumulation of type IV collagen, LN, FN, TN, and FNR was observed in the thickened capillary walls, particularly in the subendothelial layer and, to some extent, in the mesangium. However, deposits of VN were sparse and the distribution of VNR was similar to that in normal kidney. In segmental sclerotic lesions, the amounts of type IV collagen, LN, FN, VN, and TN were increased, whereas those of FNR and VNR were markedly decreased. These results suggest that the materials deposited in the subendothelial space consist of ECM components as well as of plasma-derived proteins, and that the deposition of ECM components and of FNR may be involved in the development and the reparative process of the characteristic glomerular lesions. The formation of sclerotic lesions was linked to the accumulation of ECM components, but not to an interaction with integrins.
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Affiliation(s)
- H Shiiki
- First Department of Internal Medicine, Nara Medical University, Japan
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Niemir ZI, Stein H, Noronha IL, Krüger C, Andrassy K, Ritz E, Waldherr R. PDGF and TGF-beta contribute to the natural course of human IgA glomerulonephritis. Kidney Int 1995; 48:1530-41. [PMID: 8544410 DOI: 10.1038/ki.1995.443] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
PDGF and TGF-beta are known mediators of mesangial cell proliferation and matrix expansion. The presence of these regulatory factors was examined in 30 renal biopsies from patients with IgA glomerulonephritis (IgA-GN) at the mRNA and protein level. Normal renal tissue served as control. The mRNA expression of PDGF A/B chains, PDGF-beta R and TGF-beta 1 was evaluated by means of RT/PCR with subsequent Southern blot hybridization and/or non-radioactive in situ hybridization. In addition, PDGF-AB/BB, PDGF-beta R, TGF-beta isoforms (beta 1, beta 1 + 2, beta 2 + 3), the small TGF-beta 1 latency associated peptide (TGF-beta 1 LAP) and the extracellular matrix proteins tenascin and decorin were analyzed by immunocytochemistry. The expression of growth factors was correlated with light microscopic and clinical features. Compared to normal control kidneys, an increased expression of PDGF-BB/PDGF-beta R mRNAs and the corresponding proteins was observed in all biopsies with IgA-GN. Up-regulation was related to the degree of glomerular proliferation and the extent of fibrosing interstitial lesions. In contrast, there was a discordance between TGF-beta 1 mRNA and protein expression (evaluated by immunocytochemistry). In all biopsies, irrespective of the stage of the disease, abundant TGF-beta 1 transcripts were detected, whereas TGF-beta 1 immunoreactivity was expressed to a lesser degree and disclosed a more variable staining pattern. In patients with significant proliferative glomerular lesions and minor tubulointerstitial alterations, TGF-beta 1 positivity was confined to areas of glomerular proliferation, whereas in cases with more severe histology including sclerosing lesions TGF-beta 1 immunoreactivity was less prominent. The distribution and the intensity of TGF-beta 1 LAP staining commonly exceeded the positivity noted for TGF-beta 1, indicating only limited TGF-beta 1 activation. A decreased reactivity for tenascin accompanied the morphological features of glomerular sclerosis. The staining patterns and the fact that only very few inflammatory cells, particularly CD68 positive monocytes/macrophages, were detected in glomeruli confirm that predominantly resident glomerular cells (mesangial and endothelial cells) are the major source of up-regulated growth factor production in IgA-GN. Since the expression of PDGF-AB/BB paralleled the severity of proliferative glomerular changes, PDGF seems to represent a potential indicator of activity in this condition. It is suggested that an imbalance between PDGF and TGF-beta (by restricted translation and/or activation) production contribute to the progressive nature of IgA-GN.
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Affiliation(s)
- Z I Niemir
- Department of Pathology, Ruperto-Carola University, Heidelberg, Germany
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Assmann KJ, Koene RA, Wetzels JF. Familial glomerulonephritis characterized by massive deposits of fibronectin. Am J Kidney Dis 1995; 25:781-91. [PMID: 7747733 DOI: 10.1016/0272-6386(95)90555-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In recent years more than 150 cases of glomerulonephritis characterized by deposits of irregularly arranged fibrils have been documented. In the majority of these cases immunoglobulins and complement are the prime constituents of these deposits. We recently made a diagnosis of fibrillary glomerulonephritis without immunoglobulin deposition in two members of a family, a father and a son. In the father, proteinuria was first discovered 18 years ago. In 1985 he was referred to our outpatient clinic because of hypertension and increasing proteinuria. From that time onward he was regularly seen for blood pressure control. Nephrotic-range proteinuria persisted, without hardly any evidence of deterioration of renal function. Renal biopsies were performed in 1985 and 1993. His son underwent a renal biopsy in 1993 because of moderate proteinuria. The biopsies of both patients disclosed a distinct form of fibrillary glomerulonephritis that was characterized by massive deposits of a homogeneous, eosinophilic material in the mesangial and subendothelial areas. Staining for amyloid was negative. Immunofluorescence revealed that the biopsy specimens only stained faintly for immunoglobulins, complement factors C1q and C3, the extracellular matrix proteins, collagen IV, and laminin. However, they strongly stained for fibronectin. Using monoclonal antibodies specific for cell-derived fibronectin (IST-9) and plasma- and cell-derived fibronectin (IST-4), in the biopsy of the son we demonstrated that the fibronectin deposited in the glomeruli was mainly derived from the plasma, and to a lesser extent from resident glomerular cells. In addition, a moderate staining for amyloid P and vitronectin also was present. No or minor enhanced staining for collagen I, III, or V, heparan sulfate proteoglycan or its glycosaminoglycan side chains, tenascin, or thrombospondin could be observed. By electron microscopy the deposits in the mesangium and the subendothelial spaces appeared focally to be composed of irregularly arranged fibrils or microtubules 10 to 12 nm in diameter. Fibrillary glomerulonephritis with massive deposits of fibronectin represents a rare form of familial glomerulonephritis. In our patients the glomerulonephritis has an indolent course with hardly any deterioration of renal function.
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Affiliation(s)
- K J Assmann
- Department of Pathology, University Hospital Nijmegen, The Netherlands
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