|
1
|
Latcu SC, Bardan R, Cumpanas AA, Barbos V, Baderca F, Gaje PN, Ceausu RA, Comsa S, Dumitru CS, Dumache R, Cut TG, Lazureanu VE, Petrica L. Immunotherapy Applications for Thymine Dimers and WT1 Antigen in Renal Cancers: A Comparative Statistical Analysis. J Pers Med 2024; 14:557. [PMID: 38929778 PMCID: PMC11205122 DOI: 10.3390/jpm14060557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Renal cell carcinoma (RCC) remains incurable in advanced stages. Biomarkers have proven to be quite useful in cancer therapeutics. Herein, we provide a comparative/integrative statistical analysis of seminal immunohistochemistry (IHC) findings for Wilms' Tumor 1 antigen (WT1) and thymine dimers (TDs), emerging as atypical, yet promising, potential biomarkers for RCCs. We assessed WT1/TD reactivity in adult RCC tumor cells, tumor microenvironment (TME), and tumor-adjacent healthy renal tissue (HRT). WT1 positivity was scarce and strictly nuclear in tumor cells, whereas TD-reactive tumor tissues were prevalent. We report statistically significant positive correlations between the density of reactive RCC cellularity and the intensity of nuclear staining for both biomarkers (WT1 - rho = 0.341, p-value = 0.036; TDs - rho = 0.379, p-value = 0.002). RCC stromal TME TD-positivity was much more frequent than WT1 reactivity, apparently proportional to that of the proper RCC cellularity and facilitated by extensive RCC inflammatory infiltration. TDs exhibited nuclear reactivity for most TME cell lines, while RCC TME WT1 expression was rare and inconsistent. In HRTs, TDs were entirely restricted to renal tubular cells, the likely cellular progenitor of most conventional RCC subtypes. In lieu of proper validation, these early findings have significant implications regarding the origins/biology of RCCs and may inform RCC therapeutics, both accounting for the high frequency of immunotherapy-permissive frameshift indels in RCCs, but also hinting at novel predictive clinical tools for WT1-targeted immunotherapy. Overall, the current study represents a meek yet hopefully significant step towards understanding the molecular biology and potential therapeutic targets of RCCs.
Collapse
Affiliation(s)
- Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (S.C.L.); (V.B.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Razvan Bardan
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Alin Adrian Cumpanas
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Vlad Barbos
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (S.C.L.); (V.B.)
| | - Flavia Baderca
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Pusa Nela Gaje
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Raluca Amalia Ceausu
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Serban Comsa
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Cristina-Stefania Dumitru
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Raluca Dumache
- Department VIII, Discipline of Forensic Medicine, Bioethics, Deontology and Medical Law, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Center for Ethics in Human Genetic Identifications, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Talida Georgiana Cut
- Center for Ethics in Human Genetic Identifications, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Voichita Elena Lazureanu
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Ligia Petrica
- Department of Internal Medicine II, Division of Nephrology, Victor Babes University of Medicine and Pharmacy Timisoara, County Emergency Hospital Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| |
Collapse
|
|
2
|
Novacescu D, Cut TG, Cumpanas AA, Bratosin F, Ceausu RA, Raica M. Novel Expression of Thymine Dimers in Renal Cell Carcinoma, Demonstrated through Immunohistochemistry. Biomedicines 2022; 10:2673. [PMID: 36359193 PMCID: PMC9687240 DOI: 10.3390/biomedicines10112673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/25/2022] [Accepted: 10/20/2022] [Indexed: 08/26/2023] Open
Abstract
Despite significant developments in renal cell carcinoma (RCC) detection and molecular pathology, mortality has been steadily rising. Advanced RCC remains an incurable disease. Better clinical management tools, i.e., RCC biomarkers, have yet to emerge. Thymine-dimers (TDs) were traditionally considered photo-dependent pre-mutagenic lesions, occurring exclusively during ultra-violet light exposure. Non-oxidative, direct, and preferential byproducts of DNA photochemical reactions, TDs, have recently shown evidence regarding UVR-independent formation. In this study, we investigate, for the first time, TD expression within RCC tumor tissue and tumor-adjacent healthy renal parenchyma using a TD-targeted IHC monoclonal antibody, clone KTM53. Remarkably, out of the 54 RCCs evaluated, 77.8% showed nuclear TD-expression in RCC tumor tissue and 37% in the tumor-adjacent healthy renal parenchyma. A comprehensive report regarding quantitative/qualitative TD-targeted immunostaining was elaborated. Two main distribution models for TD expression within RCC tumor tissue were identified. Statistical analysis showed significant yet moderate correlations regarding TD-positivity in RCC tissue/tumor-adjacent healthy renal parenchyma and TNM stage at diagnosis/lymphatic dissemination, respectively, indicating possible prognostic relevance. We review possible explanations for UVR-independent TD formation and molecular implications regarding RCC carcinogenesis. Further rigorous molecular analysis is required in order to fully comprehend/validate the biological significance of this newly documented TD expression in RCC.
Collapse
Affiliation(s)
- Dorin Novacescu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
| | - Talida Georgiana Cut
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Center for Ethics in Human Genetic Identifications, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
| | - Alin Adrian Cumpanas
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
| | - Felix Bratosin
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Methodological and Infectious Diseases Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
| | - Raluca Amalia Ceausu
- Department II, Discipline of Histology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
| | - Marius Raica
- Department II, Discipline of Histology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
| |
Collapse
|
|
3
|
Adeva-Andany MM, Carneiro-Freire N. Biochemical composition of the glomerular extracellular matrix in patients with diabetic kidney disease. World J Diabetes 2022; 13:498-520. [PMID: 36051430 PMCID: PMC9329837 DOI: 10.4239/wjd.v13.i7.498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/19/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
In the glomeruli, mesangial cells produce mesangial matrix while podocytes wrap glomerular capillaries with cellular extensions named foot processes and tether the glomerular basement membrane (GBM). The turnover of the mature GBM and the ability of adult podocytes to repair injured GBM are unclear. The actin cytoskeleton is a major cytoplasmic component of podocyte foot processes and links the cell to the GBM. Predominant components of the normal glomerular extracellular matrix (ECM) include glycosaminoglycans, proteoglycans, laminins, fibronectin-1, and several types of collagen. In patients with diabetes, multiorgan composition of extracellular tissues is anomalous, including the kidney, so that the constitution and arrangement of glomerular ECM is profoundly altered. In patients with diabetic kidney disease (DKD), the global quantity of glomerular ECM is increased. The level of sulfated proteoglycans is reduced while hyaluronic acid is augmented, compared to control subjects. The concentration of mesangial fibronectin-1 varies depending on the stage of DKD. Mesangial type III collagen is abundant in patients with DKD, unlike normal kidneys. The amount of type V and type VI collagens is higher in DKD and increases with the progression of the disease. The GBM contains lower amount of type IV collagen in DKD compared to normal tissue. Further, genetic variants in the α3 chain of type IV collagen may modulate susceptibility to DKD and end-stage kidney disease. Human cellular models of glomerular cells, analyses of human glomerular proteome, and improved microscopy procedures have been developed to investigate the molecular composition and organization of the human glomerular ECM.
Collapse
|
|
4
|
Zhao L, Liu F, Li L, Zhang J, Wang T, Zhang R, Zhang W, Yang X, Zeng X, Wang Y, Wu Y, Yang H, Wang S, Zhong Y, Xu H, Wang S, Guo R, Ren H, Yang L, Su B, Zhang J, Tong N, Zhou XJ, Cooper ME. Solidified glomerulosclerosis, identified using single glomerular proteomics, predicts end-stage renal disease in Chinese patients with type 2 diabetes. Sci Rep 2021; 11:4658. [PMID: 33633132 PMCID: PMC7907371 DOI: 10.1038/s41598-021-83856-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Few histological prognostic indicators for end-stage renal disease (ESRD) have been validated in diabetic patients. This biopsy-based study aimed to identify nephropathological risk factors for ESRD in Chinese patients with type 2 diabetes. Histological features of 322 Chinese type 2 diabetic patients with biopsy-confirmed diabetic nephropathy (DN) were retrospectively analysed. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) for ESRD. Single glomerular proteomics and immunohistochemistry were used to identify differentially expressed proteins and enriched pathways in glomeruli. During the median follow-up period of 24 months, 144 (45%) patients progressed to ESRD. In multivariable models, the Renal Pathology Society classification failed to predict ESRD, although the solidified glomerulosclerosis (score 1: HR 1.65, 95% confidence interval [CI] 1.04-2.60; score 2: HR 2.48, 95% CI 1.40-4.37) and extracapillary hypercellularity (HR 2.68, 95% CI 1.55-4.62) were identified as independent risk factors. Additionally, single glomerular proteomics, combined with immunohistochemistry, revealed that complement C9 and apolipoprotein E were highly expressed in solidified glomerulosclerosis. Therefore, solidified glomerulosclerosis and extracapillary hypercellularity predict diabetic ESRD in Chinese patients. Single glomerular proteomics identified solidified glomerulosclerosis as a unique pathological change that may be associated with complement overactivation and abnormal lipid metabolism.
Collapse
Affiliation(s)
- Lijun Zhao
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Fang Liu
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China.
| | - Lin Li
- Division of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Junlin Zhang
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Tingli Wang
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Rui Zhang
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Wei Zhang
- West China Biomedical Big Data Center, West China Hospital/ West China School of Medicine of Sichuan University, Chengdu, Sichuan, China
| | - Xiaoyan Yang
- West China Biomedical Big Data Center, West China Hospital/ West China School of Medicine of Sichuan University, Chengdu, Sichuan, China
| | - Xiaoxi Zeng
- West China Biomedical Big Data Center, West China Hospital/ West China School of Medicine of Sichuan University, Chengdu, Sichuan, China
| | - Yiting Wang
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Yucheng Wu
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Hao Yang
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Shisheng Wang
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yi Zhong
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Huan Xu
- Division of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Shanshan Wang
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Ruikun Guo
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Honghong Ren
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Lichuan Yang
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Baihai Su
- Division of Nephrology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan Province, China
| | - Jie Zhang
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Nanwei Tong
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xin J Zhou
- Department of Pathology, Baylor University Medical Center at Dallas, Dallas, TX, USA
| | - Mark E Cooper
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| |
Collapse
|
|
5
|
Vuiblet V, Fere M, Gobinet C, Birembaut P, Piot O, Rieu P. Renal Graft Fibrosis and Inflammation Quantification by an Automated Fourier-Transform Infrared Imaging Technique. J Am Soc Nephrol 2015; 27:2382-91. [PMID: 26683669 DOI: 10.1681/asn.2015050601] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 11/01/2015] [Indexed: 01/05/2023] Open
Abstract
Renal interstitial fibrosis and interstitial active inflammation are the main histologic features of renal allograft biopsy specimens. Fibrosis is currently assessed by semiquantitative subjective analysis, and color image analysis has been developed to improve the reliability and repeatability of this evaluation. However, these techniques fail to distinguish fibrosis from constitutive collagen or active inflammation. We developed an automatic, reproducible Fourier-transform infrared (FTIR) imaging-based technique for simultaneous quantification of fibrosis and inflammation in renal allograft biopsy specimens. We generated and validated a classification model using 49 renal biopsy specimens and subsequently tested the robustness of this classification algorithm on 166 renal grafts. Finally, we explored the clinical relevance of fibrosis quantification using FTIR imaging by comparing results with renal function at 3 months after transplantation (M3) and the variation of renal function between M3 and M12. We showed excellent robustness for fibrosis and inflammation classification, with >90% of renal biopsy specimens adequately classified by FTIR imaging. Finally, fibrosis quantification by FTIR imaging correlated with renal function at M3, and the variation in fibrosis between M3 and M12 correlated well with the variation in renal function over the same period. This study shows that FTIR-based analysis of renal graft biopsy specimens is a reproducible and reliable label-free technique for quantifying fibrosis and active inflammation. This technique seems to be more relevant than digital image analysis and promising for both research studies and routine clinical practice.
Collapse
Affiliation(s)
- Vincent Vuiblet
- Matrice Extracellulaire et Dynamique Cellulaire Unit, Centre National pour la Recherche Scientifique, Unité Mixte de Recherche 7369, and Nephrology and Renal Transplantation Department and Biopathology Laboratory, Centre Hospitalier et Universitaire de Reims, Reims, France
| | - Michael Fere
- Matrice Extracellulaire et Dynamique Cellulaire Unit, Centre National pour la Recherche Scientifique, Unité Mixte de Recherche 7369, and
| | - Cyril Gobinet
- Matrice Extracellulaire et Dynamique Cellulaire Unit, Centre National pour la Recherche Scientifique, Unité Mixte de Recherche 7369, and
| | - Philippe Birembaut
- Biopathology Laboratory, Centre Hospitalier et Universitaire de Reims, Reims, France
| | - Olivier Piot
- Matrice Extracellulaire et Dynamique Cellulaire Unit, Centre National pour la Recherche Scientifique, Unité Mixte de Recherche 7369, and Cellular and Tissular Imaging Platform, Université de Reims Champagne-Ardenne, Reims, France; and
| | - Philippe Rieu
- Matrice Extracellulaire et Dynamique Cellulaire Unit, Centre National pour la Recherche Scientifique, Unité Mixte de Recherche 7369, and Nephrology and Renal Transplantation Department and
| |
Collapse
|
|
6
|
Rørtveit R, Lingaas F, Bønsdorff T, Eggertsdóttir AV, Grøndahl AM, Thomassen R, Fogo AB, Jansen JH. A canine autosomal recessive model of collagen type III glomerulopathy. J Transl Med 2012; 92:1483-91. [PMID: 22890554 DOI: 10.1038/labinvest.2012.112] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Collagen type III glomerulopathy (Col3GP) is a rare renal disease characterized by massive glomerular accumulations of collagen type III. The disease occurs in both humans and animals, and has been presumed to be heritable with an autosomal recessive inheritance pattern. The pathogenesis is unknown. We describe herein a condition of canine autosomal recessive Col3GP. This spontaneously occurring canine disease was incidentally diagnosed in six mongrel dogs. We then established and studied a pedigree segregating the disease to confirm the genetic nature and inheritance of canine Col3GP. Twenty-nine percent of offspring (14/48) were affected, strongly supporting a simple autosomal recessive inheritance pattern. Kidney specimens were studied by light microscopy, electron microscopy (EM), immunohistochemistry and in situ hybridization. Characteristic findings of Col3GP previously reported in both humans and animals were demonstrated, including massive glomerular collagen type III deposition, and evidence of local mesangial collagen type III synthesis was found. We propose that canine Col3GP may serve as an animal model of human Col3GP. Our initial studies, using simple segregation analysis, showed that the Col3A1 gene was not involved in the disease. This is the first animal model of Col3GP, and further studies of this phenotype in dogs may have the potential to provide information on the pathogenesis and genetics of the disease in both animals and humans, and may thus contribute to the development of treatment regimes.
Collapse
Affiliation(s)
- Runa Rørtveit
- Department of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, Oslo, Norway.
| | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Taguchi T, Nazneen A, Al-Shihri AA, A. Turkistani K, Razzaque MS. Heat shock protein 47: a novel biomarker of phenotypically altered collagen-producing cells. Acta Histochem Cytochem 2011; 44:35-41. [PMID: 21614164 PMCID: PMC3096080 DOI: 10.1267/ahc.11001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 02/18/2011] [Indexed: 01/15/2023] Open
Abstract
Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that helps the molecular maturation of various types of collagens. A close association between increased expression of HSP47 and the excessive accumulation of collagens is found in various human and experimental fibrotic diseases. Increased levels of HSP47 in fibrotic diseases are thought to assist in the increased assembly of procollagen, and thereby contribute to the excessive deposition of collagens in fibrotic areas. Currently, there is not a good universal histological marker to identify collagen-producing cells. Identifying phenotypically altered collagen-producing cells is essential for the development of cell-based therapies to reduce the progression of fibrotic diseases. Since HSP47 has a single substrate, which is collagen, the HSP47 cellular expression provides a novel universal biomarker to identify phenotypically altered collagen-producing cells during wound healing and fibrosis. In this brief article, we explained why HSP47 could be used as a universal marker for identifying phenotypically altered collagen-producing cells.
Collapse
Affiliation(s)
- Takashi Taguchi
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences
| | - Arifa Nazneen
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences
| | - Abdulmonem A. Al-Shihri
- Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine
| | | | - Mohammed S. Razzaque
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine
| |
Collapse
|
|
8
|
Razzaque MS, Taguchi T. Expression of type III collagen mRNA in renal biopsy specimens of patients with idiopathic membranous glomerulonephritis. Mol Pathol 2010; 49:M40-2. [PMID: 16696043 PMCID: PMC408016 DOI: 10.1136/mp.49.1.m40] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Aim-To investigate the distribution of type III collagen in membranous glomerulonephritis (MGN); to identify the cells responsible for the synthesis of alpha1 (III) mRNA.method-The distribution of type III collagen was studied by immunohistochemistry in 10 renal biopsy specimens, histologically diagnosed as MGN, and five control renal tissue samples obtained at surgery. Synthesis of alpha1 (III) mRNA was detected by non-radioactive in situ hybridisation.Results-On immunohistochemistry, type III collagen was not observed in the control glomeruli, but was present focally in the glomeruli in samples from patients with MGN. No specific hybridisation signal for alpha1 (III) mRNA was found in the control glomeruli on non-radioactive in situ hybridisation. By contrast, positive signals for alpha1 (III) chain mRNA were detected in glomerular epithelial cells and mesangial cells in MGN tissue samples.Conclusion-These data suggest that additional synthesis of type III collagen by intraglomerular cells contributes to the changes in the glomerular basement membrane characteristic of MGN.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | | |
Collapse
|
|
9
|
Ban CR, Twigg SM, Franjic B, Brooks BA, Celermajer D, Yue DK, McLennan SV. Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction. Diabetes Res Clin Pract 2010; 87:335-41. [PMID: 20096949 DOI: 10.1016/j.diabres.2010.01.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 12/11/2009] [Accepted: 01/04/2010] [Indexed: 01/01/2023]
Abstract
Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p<0.05 vs control, in those with diastolic dysfunction), and renal filtration function (p<0.05 vs control). In summary, we have identified novel relationships between serum MMP-7 and diabetic complications specifically in renal disease and in diastolic dysfunction. How increased circulating MMP-7 is associated with these diabetic microvascular complications and the significance of these findings will require prospective studies.
Collapse
Affiliation(s)
- C R Ban
- Alesd Hospital, Bihor County, Romania
| | | | | | | | | | | | | |
Collapse
|
|
10
|
Kamiie J, Yasuno K, Ogihara K, Nakamura A, Tamahara S, Fujino Y, Ono K, Shirota K. Collagenofibrotic Glomerulonephropathy with Fibronectin Deposition in a Dog. Vet Pathol 2009; 46:688-92. [DOI: 10.1354/vp.08-vp-0272-s-cr] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
We report herein a case of collagenofibrotic glomerulonephropathy in a 3-year-old Shiba Inu with severe proteinuria. Histologically, renal glomeruli were enlarged with massive deposition of a homogeneous eosinophilic substance within the mesangium and capillary walls. The deposits reacted weakly with periodic acid-Schiff, stained deep blue with Masson's trichrome, and were positive by immunofluorescence for type III collagen and fibronectin. Ultrastructurally, the deposits consisted of fibrils and amorphous material in the mesangial matrix and beneath the glomerular capillary endothelium. The fibrils had transverse bands analogous to those of collagen fibrils. Electron microscopy also revealed focal detachment of podocytes and foot process effacement in glomerular tufts, which suggested that podocyte injury had contributed to the development of proteinuria in this dog. The current case resembles collagenofibrotic glomerulonephropathy (CFGN) in humans in histopathologic, immunofluorescence, and electron microscopic findings. This is the first report of CFGN in a nonhuman species with glomerular deposition of fibronectin and type III collagen.
Collapse
Affiliation(s)
- J. Kamiie
- Laboratory of Veterinary Pathology, Azabu University, Sagamihara, Kanagawa
| | - K. Yasuno
- Research Institute of Biosciences, Azabu University, Sagamihara, Kanagawa
| | - K. Ogihara
- Laboratory of Environmental Pathology, Azabu University, Sagamihara, Kanagawa
| | - A. Nakamura
- Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - S. Tamahara
- Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Y. Fujino
- Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - K. Ono
- Laboratory of Veterinary Clinical Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - K. Shirota
- Laboratory of Veterinary Pathology, Azabu University, Sagamihara, Kanagawa
- Research Institute of Biosciences, Azabu University, Sagamihara, Kanagawa
| |
Collapse
|
|
11
|
KOBAYASHI R, YASUNO K, OGIHARA K, YAMAKI M, KAGAWA Y, KAMIIE J, SHIROTA K. Pathological Characterization of Collagenofibrotic Glomerulonephropathy in a Young Dog. J Vet Med Sci 2009; 71:1137-41. [DOI: 10.1292/jvms.71.1137] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
| | | | | | | | | | | | - Kinji SHIROTA
- Research Institute of Biosciences, Azabu University
- Laboratory of Veterinary Pathology, Azabu University
| |
Collapse
|
|
12
|
Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 2008; 4:575-96. [PMID: 18827908 PMCID: PMC2515418 DOI: 10.2147/vhrm.s1991] [Citation(s) in RCA: 190] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus is characterized by a lack of insulin causing elevated blood glucose, often with associated insulin resistance. Over time, especially in genetically susceptible individuals, such chronic hyperglycemia can cause tissue injury. One pathological response to tissue injury is the development of fibrosis, which involves predominant extracellular matrix (ECM) accumulation. The main factors that regulate ECM in diabetes are thought to be pro-sclerotic cytokines and protease/anti-protease systems. This review will examine the key markers and regulators of tissue fibrosis in diabetes and whether their levels in biological fluids may have clinical utility.
Collapse
Affiliation(s)
- Camelia R Ban
- Discipline of Medicine and Department of Endocrinology, The University of Sydney and Royal Prince Alfred Hospital Sydney, New South Wales, 2006, Australia
| | | |
Collapse
|
|
13
|
Razzaque MS. Does renal ageing affect survival? Ageing Res Rev 2007; 6:211-22. [PMID: 17662672 DOI: 10.1016/j.arr.2007.06.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2007] [Revised: 06/25/2007] [Accepted: 06/26/2007] [Indexed: 12/31/2022]
Abstract
The effects of ageing on progressive deterioration of renal function, both in human and experimental animals, are described elsewhere, but the effect of renal damage on overall survival and longevity is not yet clearly established. The wild-type animals of various genetic backgrounds, fed with regular diet, overtime develop severe age-associated nephropathy, that include but not limited to inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis. Such renal damage significantly reduces their survival. Reducing renal damage, either by caloric restriction or by suppressing growth hormone (GH)/insulin-like growth factor-1 (IGF-1) activity could significantly enhance the longevity of these animals. Available survival studies using experimental animals clearly suggest that kidney pathology is one of the important non-neoplastic lesions that could affect overall survival, and that restoration of renal function by preventing kidney damage could significantly extend longevity. Careful long-term studies are needed to determine the human relevance of these experimental studies.
Collapse
Affiliation(s)
- M Shawkat Razzaque
- Department of Developmental Biology, Harvard School of Dental Medicine, 190 Longwood Avenue, Boston, MA 02115, USA.
| |
Collapse
|
|
14
|
Alchi B, Nishi S, Narita I, Gejyo F. Collagenofibrotic glomerulopathy: clinicopathologic overview of a rare glomerular disease. Am J Kidney Dis 2007; 49:499-506. [PMID: 17386317 DOI: 10.1053/j.ajkd.2007.01.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2006] [Accepted: 01/18/2007] [Indexed: 01/15/2023]
Abstract
Collagenofibrotic glomerulopathy is an idiopathic glomerular disease characterized by massive accumulation of atypical type III collagen fibrils within the mesangial matrix and subendothelial space and marked increase in serum type III procollagen peptide levels. The disease is extremely rare, with most cases reported in Japan. The cause and pathogenesis are entirely elusive. Some cases were described in families; hence, a genetic mode of transmission, mostly by an autosomal recessive trait, has been assumed. Controversy exists about whether the glomerulopathy is a primary renal disease or manifestation of systemic disease. Proteinuria is a cardinal manifestation of this disease. Clinically, patients present with edema and hypertension and often progress to end-stage renal disease. A definite diagnosis can be established when typical histological findings are supported by immunohistochemistry for specific collagen types and electron microscopy with special staining methods. No specific treatment is available.
Collapse
Affiliation(s)
- Bassam Alchi
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | | | | | | |
Collapse
|
|
15
|
Ikee R, Kobayashi S, Hemmi N, Saigusa T, Namikoshi T, Yamada M, Imakiire T, Kikuchi Y, Suzuki S, Miura S. Involvement of Transglutaminase-2 in Pathological Changes in Renal Disease. ACTA ACUST UNITED AC 2007; 105:c139-46. [PMID: 17228174 DOI: 10.1159/000098646] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Accepted: 10/01/2006] [Indexed: 01/15/2023]
Abstract
BACKGROUND Transglutaminase (Tg)-2 is shown to be related to renal fibrosis. However, its roles in human kidney disease have not been fully studied. METHODS Using immunohistochemistry, we examined Tg-2 expression in renal biopsy specimens from 22 patients with IgA nephropathy (IgAN) and correlated the intensity of Tg-2 staining with clinical and histopathological parameters. We compared the distribution and intensity of Tg-2 staining with those of transforming growth factor (TGF)-beta staining. RESULTS In normal human kidneys, Tg-2 staining was not significant. In IgAN kidneys, glomerular Tg-2 staining correlated with serum creatinine (S-Cr), creatinine clearance (Ccr), urinary protein excretion, glomerular sclerosis, and mesangial cell proliferation. Tubulointerstitial Tg-2 correlated with S-Cr, Ccr, N-acetyl-beta-glucosaminidase, urinary beta(2)-microglobulin, and tubulointerstitial injuries. Tg-2 staining in the vicinity of vascular poles of glomeruli preceded the development of mesangial lesions, and was more remarkable in cases with renal impairment. The distribution and intensity of Tg-2 staining were not consistent with those of TGF-beta staining. In glomerular crescents, Tg-2 staining was remarkable. CONCLUSION The present study showed a correlation between Tg-2 expression and renal function and pathological changes. Tg-2 expression in the vicinity of vascular poles was notable because that may be an initial marker of glomerular injury.
Collapse
Affiliation(s)
- Ryota Ikee
- Second Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Abstract
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix proteins in the mesangium and basement membrane of the glomerulus and in the renal tubulointerstitium. This review summarizes the main changes in protein composition of the glomerular mesangium and basement membrane and the evidence that, in the mesangium, these are initiated by changes in glucose metabolism and the formation of advanced glycation end products. Both processes generate reactive oxygen species (ROS). The review includes discussion of how ROS may activate intracellular signaling pathways leading to the activation of redox-sensitive transcription factors. This in turn leads to change in the expression of genes encoding extracellular matrix proteins and the protease systems responsible for their turnover.
Collapse
Affiliation(s)
- Roger M Mason
- Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
| | | |
Collapse
|
|
17
|
Abstract
Connective tissue remodeling of the interstitium is an important feature of chronic lung diseases encompassing interstitial inflammatory changes and subsequent pulmonary fibrosis. The early inflammatory phase is usually associated with the release of several cytokines and chemokines by activated resident cells and infiltrating cells which, in turn, help further recruit inflammatory mononuclear cells. Cytokines and growth factors secreted by inflammatory cells and by interstitial cells (fibroblasts and myofibroblasts) play an important role in the fibrogenic phase of pulmonary fibrosis by inducing matrix synthesis. In addition, matrix-degrading enzymes and their inhibitors also contribute to extracellular matrix (ECM) remodeling in pulmonary fibrosis. This review addresses the pathophysiology of wound healing and different phases of pulmonary fibrosis.
Collapse
Affiliation(s)
- Mohammed S Razzaque
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
| | | |
Collapse
|
|
18
|
Kobayashi M, Kimura H, Liao J, Abe M, Hirose S, Tomino Y. Measurement of mouse urinary type IV collagen using time-resolved fluoroimmunoassay. ANAL SCI 2003; 19:205-10. [PMID: 12608746 DOI: 10.2116/analsci.19.205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Urinary level of type IV collagen is an important indicator for early renal dysfunction, but there has been no practical system to measure mouse type IV collagen adaptable to extremely small amounts of urine samples. We developed a highly sensitive time-resolved fluoroimmunoassay (TR-FIA) to measure mouse urinary type IV collagen. Based on the structural features of type IV collagen molecule, dithiothreitol (DTT) was used for pretreatment of the samples. This assay permits measurement of 100 pg/ml type IV collagen in 5 microl urine samples. Urinary levels of type IV collagen derived from 12 samples of two different mouse strains (KK/Ta and BALB/c) were measured using this assay. The results demonstrated very clearly the difference in values of urinary type IV collagen between diabetic mice and non-diabetic mice. Compared with the conventional enzyme-linked immunosorbent assay (ELISA), this method requires far smaller volumes of samples, and is best suited to mouse models in future experiments.
Collapse
Affiliation(s)
- Michimasa Kobayashi
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | | | | | | | | | | |
Collapse
|
|
19
|
Adler SG, Kang SW, Feld S, Cha DR, Barba L, Striker L, Striker G, Riser BL, LaPage J, Nast CC. Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy. Kidney Int 2001; 60:2330-6. [PMID: 11737607 DOI: 10.1046/j.1523-1755.2001.00073.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND In patients with type 1 diabetes, some consider microalbuminuria to be a predictor of diabetic nephropathy while others believe it is an early feature of diabetic nephropathy. METHODS Levels of mRNAs that are of pathogenetic relevance in diabetic nephropathy were compared in glomeruli isolated from microalbuminuric and overtly proteinuric subjects and in control normoalbuminuric diabetic subjects and living renal transplant donors. RESULTS In subjects with microalbuminuria and overt proteinuria, glomerular mRNAs were virtually identical and approximately twofold higher for connective tissue growth factor (CTGF; P < 0.01) and collagen alpha2(IV) (P < 0.03) compared to living renal donors and normoalbuminuric patients. Glomerular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels were not significantly different among the groups (P = 0.4). Weak but statistically significant correlations were noted between CTGF mRNA and albuminuria (assessed by rank), fractional mesangial surface area, and a composite renal biopsy index. Glomerular CTGF mRNA correlated inversely with creatinine clearance. Glomerular collagen alpha2(IV) mRNA levels correlated with albuminuria (by rank) and less strongly with fractional mesangial area. CONCLUSION To our knowledge, these data provide the first biochemical evidence demonstrating that the glomeruli of microalbuminuric patients and those with overt proteinuria do not differ significantly. The data support the concept that microalbuminuria is not "predictive" of diabetic nephropathy, but rather is an earlier point in the spectrum of diabetic nephropathy.
Collapse
Affiliation(s)
- S G Adler
- Division of Nephrology and Hypertension, Harbor-UCLA Research and Education Institute, Torrance, CA 90502, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Miyata M, Biro S, Kaieda H, Eto H, Orihara K, Kihara T, Obata H, Matsushita N, Matsuyama T, Tei C. Apolipoprotein J/clusterin is induced in vascular smooth muscle cells after vascular injury. Circulation 2001; 104:1407-12. [PMID: 11560857 DOI: 10.1161/hc3701.095583] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Understanding the precise molecular mechanisms underlying the phenomenon of restenosis after PTCA may help us to develop a new strategy for the treatment of restenosis after PTCA. The purpose of this study was to identify the genes involved in vascular restenosis. METHODS AND RESULTS Applying a differential hybridization method to a model of the balloon-injured rabbit aorta, we identified 6 cDNA clones that were upregulated after injury. Northern blot showed that 5 genes, but not apolipoprotein J (apoJ)/clusterin, were constitutively expressed in noninjured aorta and upregulated after balloon injury. ApoJ mRNA was not detectable in noninjured aorta (control), began to be expressed at 6 hours after injury, showed a peak level at 24 hours (a 48-fold increase), gradually declined, and returned to the control level at 24 weeks. Western blot and immunohistochemistry demonstrated no expression of apoJ protein in noninjured aorta, an expression of apoJ at 2 days after balloon injury, and a peak level (a 55-fold increase) at 2 to 8 weeks. The expression of apoJ protein continued until 24 weeks after injury. In situ hybridization revealed that apoJ mRNA was expressed in smooth muscle cells (SMCs) of media at 2 days after injury and in SMCs of media and neointima at 2 weeks. To analyze the function of apoJ, stably transfected rabbit SMCs were created. The expression of apoJ stimulated proliferation and migration of SMCs. CONCLUSIONS ApoJ is dramatically induced in media and neointima after vascular injury, suggesting that apoJ contributes to restenosis after angioplasty.
Collapse
MESH Headings
- Angioplasty, Balloon, Coronary/adverse effects
- Animals
- Aorta/injuries
- Aorta/metabolism
- Aorta/pathology
- Aortic Diseases/etiology
- Aortic Diseases/metabolism
- Aortic Diseases/pathology
- Blotting, Western
- Cell Division/drug effects
- Cell Movement/drug effects
- Cells, Cultured
- Clusterin
- Disease Models, Animal
- Gene Expression Profiling
- Gene Expression Regulation
- Glycoproteins/biosynthesis
- Glycoproteins/genetics
- Glycoproteins/pharmacology
- Immunohistochemistry
- In Situ Hybridization
- Male
- Molecular Chaperones/biosynthesis
- Molecular Chaperones/genetics
- Molecular Chaperones/pharmacology
- Molecular Sequence Data
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- RNA, Messenger/biosynthesis
- Rabbits
- Sequence Analysis, DNA
Collapse
Affiliation(s)
- M Miyata
- First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Naito T, Razzaque MS, Nazneen A, Liu D, Nihei H, Koji T, Taguchi T. Renal expression of the Ets-1 proto-oncogene during progression of rat crescentic glomerulonephritis. J Am Soc Nephrol 2000; 11:2243-2255. [PMID: 11095647 DOI: 10.1681/asn.v11122243] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The ets-1 proto-oncogene is a member of the transcriptional factor family and was identified by homology to the v-ets oncogene. It was recently demonstrated that Ets-1 protein interacts with the promoter region of the genes coding for proteinases, including matrix metalloproteinase-1 (MMP-1), MMP-3, and urokinase-type plasminogen activator, suggesting that it may play an important role in the regulation of MMP expression. The role of the ets-1 proto-oncogene in advanced glomerular diseases, where extracellular matrix accumulation is observed, remains undefined. In this study, the expression of ets-1 mRNA and protein during the progression of rat crescentic glomerulonephritis was examined using immunohistochemical analysis, reverse transcription-PCR, and in situ hybridization. Passive accelerated anti-glomerular basement membrane-induced nephritis was induced in rats by intravenous injection of nephrotoxic serum. Rats were euthanized on day 7, 14, 21, 28, or 42. Immunohistochemical analysis demonstrated significant upregulation of Ets-1 protein expression in glomeruli and the interstitium in anti-glomerular basement membrane-induced nephritis. The numbers of Ets-1-positive cells were increased 8.8-fold on day 21 in glomeruli (1.2+/-0.1 cells/glomerular cross-section, P<0.001) and sixfold on day 28 in the interstitium (21+/-1.3 cells/mm(2), P<0.001), compared with control samples. Ets-1 protein was predominantly localized in glomerular epithelial cells, endothelial cells, and interstitial cells. A small number of vascular endothelial cells, macrophages, and T cells also expressed Ets-1 protein. MMP-3 deposition was upregulated and positive cells in the interstitium often coexpressed Ets-1, whereas only a few glomerular cells were positive for both MMP-3 and Ets-1 protein. The expression of ets-1 mRNA was also markedly increased in diseased kidneys. The distribution of ets-1 mRNA was similar to that of the protein. These results indicate that overexpression of the ets-1 proto-oncogene by phenotypically altered renal cells might be associated with the pathogenesis of rat crescentic glomerulonephritis.
Collapse
Affiliation(s)
- Takashi Naito
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
- Department of Medicine, Kidney Center, Tokyo Women's Medical College, Tokyo, Japan
| | - Mohammed S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Arifa Nazneen
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Diange Liu
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Hiroshi Nihei
- Department of Medicine, Kidney Center, Tokyo Women's Medical College, Tokyo, Japan
| | - Takehiko Koji
- Department of Histology and Cell Biology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - Takashi Taguchi
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| |
Collapse
|
|
22
|
Adler SG, Feld S, Striker L, Striker G, LaPage J, Esposito C, Aboulhosn J, Barba L, Cha DR, Nast CC. Glomerular type IV collagen in patients with diabetic nephropathy with and without additional glomerular disease. Kidney Int 2000; 57:2084-92. [PMID: 10792628 DOI: 10.1046/j.1523-1755.2000.00058.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Type IV collagen is a constituent of mesangial matrix and is increased in amount in many forms of glomerular injury. METHODS We performed renal biopsies in patients who (1) were donating a kidney to a relative (LRD, N = 6), (2) had diabetic glomerulopathy with or without nephrosclerosis (DM, N = 6), or (3) had diabetic glomerulopathy with a superimposed glomerular lesion (DM+, N = 5). Glomerular collagen alpha2(IV) and control glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs were measured, and the former correlated with clinical and morphological data to assess its usefulness in reflecting glomerular injury. RESULTS Collagen alpha2(IV) mRNA levels were lowest in LRD (2.9 +/- 0.6 attomol/glomerulus), higher in DM (5.9 +/- 1.6, P = 0.05), and highest in DM+ (12.7 +/- 2.8 attm/glomerulus, P < 0.05 vs. LRD and vs. DM). Control GAPDH mRNA levels were not significantly different (P > 0.05). Levels of proteinuria, serum creatinine, and glomerular size did not correlate with collagen alpha2(IV) mRNA levels. The fractional mesangial area and the fractional mesangial area occupied by type IV collagen were higher in both diabetic groups than in LRD (P < 10-6), but the intensity of type IV collagen staining in the diabetic patients was significantly less than that seen in the LRD (P < 0.01). In DM+ patients, extramesangial type IV collagen was present. Fractional mesangial area and glomerular collagen alpha2(IV) mRNA levels correlated (r = 0.45, P < 0.05). CONCLUSION These data are consistent with a view of diabetic nephropathy as a lesion of increased alpha2 type IV collagen transcription, increased total amount of collagen present, but decreased mesangial density relative to other matrix molecules. These data further demonstrate that glomerular injury superimposed on diabetic nephropathy contributes to additional structural damage by inducing increased synthesis of type IV collagen at extramesangial sites.
Collapse
Affiliation(s)
- S G Adler
- Harbor-UCLA Research and Education Institute, Torrance, CA 90509, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Razzaque MS, Shimokawa I, Nazneen A, Liu D, Naito T, Higami Y, Taguchi T. Life-long dietary restriction modulates the expression of collagens and collagen-binding heat shock protein 47 in aged Fischer 344 rat kidney. THE HISTOCHEMICAL JOURNAL 1999; 31:123-32. [PMID: 10416684 DOI: 10.1023/a:1003578928487] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
It has been shown that the expression of HSP47 and collagens is substantially increased in the sclerotic/fibrotic process in various organs, including kidney. However, the factors regulating the increased expression of HSP47 are not yet clear. In this study, we examined the effect of dietary restriction for the expression of collagens and collagen-binding HSP47 in the kidneys of 6- and 24-month-old male Fischer 344 (F 344) rats fed ad libitum or 30% diet-restricted. No significant histological alteration was found in the kidneys of 6-month-old fed or diet-restricted rats. Kidneys obtained from 24-month-old freely fed rats showed glomerulosclerosis with marked tubulointerstitial damage including interstitial fibrosis, while in the kidneys of 24-month-old diet-restricted rats, renal damage was remarkably less than those noted in 24-month-old freely fed rat kidneys. Immunohistochemical analysis showed an increased accumulation of type I, type III and type IV collagens in areas of glomerulosclerosis and interstitial fibrosis in old rat kidneys. Dietary restriction significantly reduces renal accumulation of collagens in old age. Aging enhanced expression of HSP47 in 24-month-old freely fed rat kidneys whereas dietary restriction suppressed its expression in 24-month-old diet-restricted rat kidneys. Also, phenotypic alterations of mesangial cells and interstitial cells (immunopositive for alpha-smooth muscle actin), glomerular epithelial cells (immunopositive for desmin) and tubular epithelial cells (immunopositive for vimentin) were seen in 24-month-old freely fed rat kidneys and found to express HSP47. Dietary restriction significantly diminished phenotypically altered renal cells in 24-month-old rat kidneys. Our results suggest that increased expression of HSP47 is associated with age-related renal damage and that diet-restricted alteration of its expression is associated with the modulation of age-associated renal sclerosis/fibrosis.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Yasuda T, Imai H, Nakamoto Y, Ohtani H, Komatsuda A, Wakui H, Miura AB. Collagenofibrotic glomerulopathy: a systemic disease. Am J Kidney Dis 1999; 33:123-7. [PMID: 9915277 DOI: 10.1016/s0272-6386(99)70267-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Collagenofibrotic glomerulopathy is a recently discovered entity that is characterized by massive accumulation of spiraled and frayed collagen fibrils in mesangial and subendothelial areas, and elevated serum levels of procollagen III peptide. We report the autopsy of a patient who received continuous ambulatory peritoneal dialysis (CAPD) therapy for 7 years. Autopsy disclosed that massive accumulation of peculiar collagen fibers was found not only in the kidney, but also in many organs including spleen, liver, myocardium, and thyroid gland. Although the possibility remains that CAPD for 7 years might change or aggravate the deposition of abnormal collagen, the current case suggests a possibility that collagenofibrotic glomerulopathy is a systemic disorder with abnormal metabolism of type III collagen.
Collapse
Affiliation(s)
- T Yasuda
- Third Department of Internal Medicine, Akita University School of Medicine, Akita City, Japan
| | | | | | | | | | | | | |
Collapse
|
|
25
|
CHENG, RAZZAQUE, NAZNEEN, TAGUCHI. Expression of the heat shock protein 47 in gentamicin-treated rat kidneys. Int J Exp Pathol 1998; 79:125-32. [PMID: 9741354 PMCID: PMC3220380 DOI: 10.1046/j.1365-2613.1998.00056.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Heat-shock proteins (HSPs) are rapidly synthesized in cells in response to various cytotoxic agents. Although several stress proteins are actively involved in the gentamicin-induced renal damages, the possible role of HSP47 in this condition is not yet clear. In this study, the expression of HSP47 in the gentamicin nephrotoxicity was examined by immunohistochemistry. Twenty male Wistar rats were sacrificed at day 0, 3, 7, 14 and 28 after subcutaneous injection of gentamicin. Gentamicin treatment causes tubular necrosis at day 3, followed by tubular regenerative changes and interstitial fibrosis, which was most prominent at day 14. The renal structures returned to almost normal architectures at day 28. By immunohistochemistry, HSP47 was weakly expressed in most of the glomeruli and occasionally in interstitial cells in the control rat kidneys. In contrast, strong immunostaining for HSP47 was noted in the tubular epithelial cells and interstitial cells in gentamicin treated rat kidneys, and strongest staining was observed at day 7. The immunostaining for HSP47 then gradually decreased, and returned to the normal level at day 28. In the whole experimental period staining pattern of HSP47 in the glomeruli was not changed. In addition, phenotypically altered tubulointerstitial cells including regenerative tubular epithelial cells (immuno-positive for vimentin) and interstitial cells (immuno-positive for alpha-smooth muscle actin) were found in gentamicin nephrotoxicity. Expression of type III collagen increased in the areas of interstitial fibrosis. By double immunostaining, the regenerated and phenotypically altered tubulointerstitial cells were found to express HSP47 in and around interstitial fibrosis. It is concluded that overexpression of HSP47 by phenotypically altered renal cells might play a significant role in the development of gentamicin nephrotoxicity.
Collapse
Affiliation(s)
- CHENG
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - RAZZAQUE
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - NAZNEEN
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| | - TAGUCHI
- Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan
| |
Collapse
|
|
26
|
MIYAZAKI M, SUZUKI D, KOJI T, YANO N, YAGAME M, ENDOH M, NOMOTO Y, NIKOLIC-PATERSON DJ, ATKINS RC, SAKAI H. Intrarenal synthesis of IL-6 in IgA nephropathy. Nephrology (Carlton) 1997. [DOI: 10.1111/j.1440-1797.1997.tb00265.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
|
|
27
|
Hattori M, Horita S, Yoshioka T, Yamaguchi Y, Kawaguchi H, Ito K. Mesangial phenotypic changes associated with cellular lesions in primary focal segmental glomerulosclerosis. Am J Kidney Dis 1997; 30:632-8. [PMID: 9370177 DOI: 10.1016/s0272-6386(97)90486-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Injury to glomerular visceral epithelial cells has been proposed as the initial step in glomerular scar formation in primary focal segmental glomerulosclerosis (FSGS); however, the subsequent process that ultimately results in glomerular scar formation remains uncertain. This study examined whether phenotypically altered mesangial cells determine the early progression of primary FSGS. Cellular lesion characterized by proliferative epithelial cell reaction with occasional endocapillary hypercellularity has been considered to be an early morphologic feature in the development of glomerular scar in primary FSGS. We compared the immunohistologic findings of 10 patients with primary FSGS showing cellular lesion, 15 patients with primary FSGS showing only segmental scar, and 10 patients with minimal-change nephrotic syndrome. Histologically normal kidney tissue samples obtained from three patients with renal trauma were used as normal controls. Alpha-smooth muscle actin expression detected by a mouse anti-human monoclonal antibody as well as de novo type III collagen expression determined by a goat polyclonal antibody were prominent in the glomerular tufts with cellular lesions in FSGS patients. A significant increase in the number of glomerular CD68+ (a mouse anti-human monoclonal antibody) macrophages was also observed in association with the cellular lesion. Repeat renal biopsies in six of the 10 FSGS patients with a cellular lesion showed disappearance of the cellular lesion, reduced glomerular alpha-smooth muscle actin expression, decreased number of glomerular CD68+ macrophage, and progression of glomerular scar formation. These results indicate that mesangial cells undergo phenotypic changes to myofibroblasts in association with the cellular lesion in primary FSGS. Thus, the phenotypically altered mesangial cells acquiring features of a myofibroblast may have an important role in the early process of glomerular scar formation in certain types of primary FSGS.
Collapse
Affiliation(s)
- M Hattori
- Department of Pediatric Nephrology, Kidney Center, Tokyo Women's Medical College, Japan
| | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
An increased accumulation of extracellular matrix (ECM), predominantly collagens, is the main component of the expanded mesangial matrix in anti-thymocyte serum (ATS)-induced glomerulonephritis (GN). Heat shock protein (HSP) 47 is a collagen-binding stress protein and has been shown to have a specific role in the intracellular processing of procollagen molecules. It is a collagen-specific molecular chaperone in various organs, but its role in the kidney in relation to matrix expansion is not yet known. This study was designed to assess whether increased ECM accumulation in ATS-induced GN is associated with HSP47. The expression of type I, type III and type IV collagens, with their molecular chaperone HSP47, was investigated in ATS-induced GN rat kidneys. Fifteen male Wistar rats were divided into two groups: ATS-induced GN rats (group I) and age-matched controls (group II). GN was induced by injecting a single dose of ATS (0.8 ml/100 g body weight). All the rats were killed on the third and tenth day of the experiment. In group I, 3 days after ATS injection, histological examination revealed a reduction in glomerular cell number with mesangiolysis. However, 10 days after ATS injection, histologically severe mesangial cell proliferation with expansion of the mesangial matrix was noted in group I rats. By semiquantitative analysis, compared with controls, increased type I, type III, and type IV collagen immunostaining was observed in the expanded mesangial matrix in ATS-induced GN (group I) rats on day 10. Immunoreactive HSP47 expression was weak in the intraglomerular cells and was occasionally seen in the interstitial cells in control kidneys. In contrast, strong immunostaining for HSP47 was noted in the glomeruli of the ATS-treated rat kidneys on day 10. In this study, there was a parallel increase of various collagens and their molecular chaperone HSP47 in the ATS-treated rat kidneys. Compared with controls, no significant difference in HSP47 expression was found in the ATS-treated rat kidneys without mesangial matrix expansion (3 days after ATS injection). It is concluded that overexpression of HSP47 might play a significant role in the excessive assembly of collagens and could subsequently contribute to the expansion of mesangial matrix found in ATS-treated rat kidneys.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan.
| | | |
Collapse
|
|
29
|
Rüger BM, Hasan Q, Greenhill NS, Davis PF, Dunbar PR, Neale TJ. Mast cells and type VIII collagen in human diabetic nephropathy. Diabetologia 1996; 39:1215-22. [PMID: 8897010 DOI: 10.1007/bf02658509] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Renal injury in diabetes mellitus is associated with progressive interstitial fibrosis and extracellular matrix accumulation. However, the phenotypes of cells forming the interstitial infiltrate in diabetic nephropathy have not been precisely defined. There is increasing evidence for the association of mast cells with angiogenesis, chronic inflammatory conditions and fibrosis. We have recently shown that human mast cells can produce the non-fibrillar short chain type VIII collagen in vivo. Using immunohistochemistry, in situ hybridisation and reverse transcriptase-polymerase chain reaction, we examined the contribution of mast cells and type VIII collagen to the fibrotic changes occurring in biopsy-proven diabetic nephropathy. We observed that the number of interstitial mast cells was significantly increased in diabetic nephropathy compared with normal kidney tissue. In specimens from diabetic subjects, intense immunohistochemical staining for type VIII collagen was detected in mast cells, on periglomerular fibres and in perivascular and interstitial sites. The expression of type VIII collagen in periglomerular and interstitial sites coincided with that of alpha smooth muscle actin, a marker for myofibroblastic differentiation mRNA for type VIII collagen was detected by reverse transcriptase-polymerase chain reaction in diabetic nephropathy and in a human mast cell line. By in situ hybridisation the transcripts for type VIII collagen were localised to renal mast cells. The increased number of mast cells and the elevated type VIII collagen deposition in human diabetic nephropathy provides a potential link between the extracellular matrix accumulation and the fibrosis observed in this condition.
Collapse
Affiliation(s)
- B M Rüger
- Department of Medicine, Wellington School of Medicine, New Zealand
| | | | | | | | | | | |
Collapse
|
|
30
|
Razzaque MS, Harada T, Taguchi T. Significance of increased accumulation of type VI collagen and transforming growth factor beta 1 in tubulointerstitial damage in hypertensive nephrosclerosis: an immunohistochemical study. J Int Med Res 1996; 24:199-208. [PMID: 8737230 DOI: 10.1177/030006059602400204] [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: 02/01/2023] Open
Abstract
The distribution of type VI collagen and transforming growth factor beta 1 (TGF beta 1) was studied by immunohistochemistry in 12 renal biopsy specimens of hypertensive nephrosclerosis and five control cases. In control kidneys, the immunostaining of type VI collagen was found in the mesangium, glomerular basement membrane and tubular basement membrane. For TGF beta 1, mesangium, glomerular basement membrane, tubular basement membrane and tubular epithelial cells stained positively in the control kidneys. In contrast to the control cases, markedly increased immunostaining for both type VI collagen and TGF beta 1 was consistently observed in tubulointerstitial damage in hypertensive nephrosclerosis. These immunohistochemical findings provide the evidence for a parallel increase of both type VI collagen and TGF beta 1 during the process of tubulointerstitial injury in hypertensive nephrosclerosis. From the results of the present study, it is speculated that TGF beta 1 may contribute to the tubulointerstitial injury by stimulating increased synthesis of various extracellular matrix including type VI collagen.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan
| | | | | |
Collapse
|
|
31
|
Razzaque MS, Cheng M, Taguchi T. Trapidil modifies mesangial cell proliferation and collagen accumulation in anti-thymocyte serum (ATS)-induced glomerulonephritis. J Comp Pathol 1996; 114:175-82. [PMID: 8920217 DOI: 10.1016/s0021-9975(96)80006-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This study was designed to assess whether the glomerular mesangial-cell proliferation and the increased extracellular matrix (ECM) accumulation that occur in anti-thymocyte serum (ATS)-induced glomerulonephritis (GN) are affected by Trapidil, a potent antagonist for platelet-derived growth factor (PDGF). Fifteen male Wistar rats were divided into three groups. In group I, GN was induced by injecting a single dose of ATS. In group II, rats were given a single dose of ATS followed by daily treatment with Trapidil. In group III, the rats (controls) were treated with a single dose of phosphate buffered saline. All the rats were killed on the 10th day of the experiment. ATS induced marked mesangial cell proliferation (P < 0.01) in group I rats and Trapidil treatment (group II) significantly suppressed such proliferation (P < 0.01). Increased type III and IV collagen immunolabelling was observed in the expanded mesangial matrix in group I rats. In group II, immunolabelling for type III and IV collagen was much less than in group I. The study suggests that Trapidil therapy is effective in suppressing both mesangial cell proliferation and mesangial matrix expansion by reducing collagen accumulation.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan
| | | | | |
Collapse
|
|
32
|
Razzaque MS, Cheng M, Horita Y, Nishihara M, Harada T, Taguchi T. Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis. J Int Med Res 1995; 23:480-6. [PMID: 8746616 DOI: 10.1177/030006059502300610] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Prolonged hypertension causes structural changes including glomerulosclerosis and tubulointerstitial damage of the kidney, termed benign nephrosclerosis. It is generally accepted that, in benign nephrosclerosis, increased accumulation of extracellular matrix in the glomeruli results in glomerulosclerosis. Little is known, however, about the possible role of the extracellular matrix in the tubulointerstitial damage in benign nephrosclerosis. In this study, the possible roles of type IV basement-membrane collagen and type III interstitial collagen in tubulointerstitial damage caused by hypertension were explored. Immunohistochemical techniques were used to investigate the distribution of type III and type IV collagens in the kidney sections of 15 patients with benign nephrosclerosis with tubulointerstitial damage and in 10 controls. In the control renal sections strong immunostaining for type III collagen was found in the interstitium and immunostaining for type IV collagen was present in the tubular basement membrane and weakly in the interstitium. In the patients with tubulointerstitial damage there was increased immunostaining for both type III and type IV collagens in the expanded interstitium and damaged tubules than was found in the control kidney sections. These findings indicate that increased accumulation of both type III and type IV collagens might play a significant role in the tubulointerstitial damage in benign nephrosclerosis.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan
| | | | | | | | | | | |
Collapse
|
|
33
|
Razzaque MS, Cheng M, Taguchi T. Suppression of mesangial-cell proliferation by trapidil in glomerulonephritis induced by anti-thymocyte serum in rats. J Int Med Res 1995; 23:458-66. [PMID: 8746613 DOI: 10.1177/030006059502300607] [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: 02/01/2023] Open
Abstract
Trapadil (Mochida Pharmaceuticals, Japan), an antiplatelet drug, suppresses the growth of several cell types and is thought to antagonize platelet-derived growth factor. The effects of trapidil on mesangial-cell proliferation in glomerulonephritis induced by anti-thymocyte serum in Wistar rats were investigated. Control rats were treated with phosphate-buffered saline (group I); group II rats were injected with a single dose of anti-thymocyte serum (8 ml/kg body weight), and group III rats were treated with both a single dose of anti-thymocyte serum (8 ml/kg body weight) and with trapidil (5 mg/kg body weight/day). Three rats in each group were killed on day 3, and the other three on day 10. Control rats showed no significant histological changes on day 3 or day 10. In group II, on day 3, there was a marked decrease in glomerular cell numbers, with mesangiolysis. Histologically severe mesangial-cell proliferation with expansion of mesangial areas was noted on day 10. None of the rats in group III showed mesangial alterations, histologically, indicating that mesangial-cell proliferation was suppressed by trapidil. This suppression may result from antagonism of the binding of platelet-derived growth factor to the specific surface receptors in the mesangial cells. Trapidil may have clinical value in the treatment of mesangial-cell proliferative glomerular diseases.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan
| | | | | |
Collapse
|
|
34
|
Razzaque MS, Koji T, Horita Y, Nishihara M, Harada T, Nakane PK, Taguchi T. Synthesis of type III collagen and type IV collagen by tubular epithelial cells in diabetic nephropathy. Pathol Res Pract 1995; 191:1099-104. [PMID: 8822111 DOI: 10.1016/s0344-0338(11)80654-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Overproduction of extracellular matrix (ECM) is considered to be primarily responsible for both glomerular and tubulointerstitial (TI) changes in diabetic nephropathy (DN). To clarify the possible role of the collagens in TI damage in DN, type III interstitial collagen and type IV basement membrane collagen were studied in 10 cases of DN and 10 control cases by immunohistochemistry and in situ hybridization techniques. In control cases, no immunostaining for type III collagen was found in the renal tubules, while strongly positive in the adjacent interstitium. On the other hand, type IV collagen was found weakly in the tubular basement membrane (TBM) in control cases. In DN, increased immunostaining for both type III and type IV collagens were found in the damaged tubulointenstitium (TI). To determine the sources of these collagens in TI damage, non-radioactive in situ hybridization was performed utilizing thymine-thymine (T-T) dimerized synthetic oligonucleotides complementary to either human pro alpha 1 (III) chain or pro alpha 1 (IV) chain mRNA as probe. In normal tubules, tubular epithelial cells were not uniformly but persistently positive for pro alpha 1 (IV) mRNA. Meanwhile, no specifically detectable positive hybridization signals for pro alpha 1 (III) mRNA was found in the normal tubular epithelial cells. Accelerated synthesis of both type III and type IV collagens by tubular epithelial cells was noted in TI damage in DN. From the results we concluded that excessive synthesis of both type III and type IV collagens by tubular epithelial cells might significantly contribute to the TI damage found in DN.
Collapse
Affiliation(s)
- M S Razzaque
- Second Department of Pathology, Nagasaki University School of Medicine, Japan
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Razzaque MS, Taguchi T. Increased expression of type III and type IV collagen in diabetic nephropathy. Diabetologia 1995; 38:632-3. [PMID: 7489852 DOI: 10.1007/bf00400738] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
|
|
36
|
Razzaque MS, Koji T, Harada T, Nakane PK, Taguchi T. Primary focal segmental glomerulosclerosis is associated with increased intraglomerular type IV collagen synthesis. Clin Chim Acta 1995; 235:121-4. [PMID: 7634489 DOI: 10.1016/0009-8981(95)06018-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
|