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Salvadori M, Rosso G. What is new in the pathogenesis and treatment of IgA glomerulonephritis. World J Nephrol 2024; 13:98709. [PMID: 39723359 PMCID: PMC11572654 DOI: 10.5527/wjn.v13.i4.98709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 11/07/2024] Open
Abstract
Recently, new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis. The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease. All these new genes apply to each of the four hits. Additionally, new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis. The IgA treatment is also changed included the future possibilities. The treatment of the chronic kidney disease, associated with the nephropathy, is mandatory, since the beginning of the disease. The classical immunosuppressive agents have poor effect. The corticosteroids remain an important cornerstone in any phase of the disease. More effect is related to the treatment of B cells and plasma cells. In particular, in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents. Most of these studies are to date in phase II/III. Finally, new agents targeting complement are arising. These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, Florence 50143, Toscana, Italy
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2
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Tamura H. IgA nephropathy associated with Crohn's disease. World J Methodol 2023; 13:67-78. [PMID: 37456980 PMCID: PMC10348078 DOI: 10.5662/wjm.v13.i3.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/16/2023] [Accepted: 05/12/2023] [Indexed: 06/20/2023] Open
Abstract
The relationship between IgA nephropathy (IgAN) and Crohn’s disease was reported. IgAN is the most common primary glomerulonephritis and one of the leading causes of chronic kidney disease and end-stage renal failure, and up to 50% of cases progressed to end-stage renal disease within 25 years after IgAN diagnosis. However, specific and effective therapeutic strategies are still lacking. In this review, we discuss the possibility of the mechanism involved in IgAN associated with Crohn’s disease based on the findings of basic and clinical studies. Although the etiology of IgAN associated with Crohn’s disease is not permanent and various factors are thought to be involved, the stabilization of the disease condition of Crohn’s disease is believed to help treat IgAN.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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3
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Ohyama Y, Yamaguchi H, Ogata S, Chiurlia S, Cox SN, Kouri NM, Stangou MJ, Nakajima K, Hayashi H, Inaguma D, Hasegawa M, Yuzawa Y, Tsuboi N, Renfrow MB, Novak J, Papagianni AA, Schena FP, Takahashi K. Racial heterogeneity of IgA1 hinge-region O-glycoforms in patients with IgA nephropathy. iScience 2022; 25:105223. [PMID: 36277451 PMCID: PMC9583103 DOI: 10.1016/j.isci.2022.105223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/22/2022] [Accepted: 09/23/2022] [Indexed: 11/23/2022] Open
Abstract
Galactose (Gal)-deficient IgA1 (Gd-IgA1) is involved in IgA nephropathy (IgAN) pathogenesis. To reflect racial differences in clinical characteristics, we assessed disease- and race-specific heterogeneity in the O-glycosylation of the IgA1 hinge region (HR). We determined serum Gd-IgA1 levels in Caucasians (healthy controls [HCs], n = 31; IgAN patients, n = 63) and Asians (HCs, n = 20; IgAN patients, n = 60) and analyzed profiles of serum IgA1 HR O-glycoforms. Elevated serum Gd-IgA1 levels and reduced number of Gal residues per HR were observed in Caucasians. Reduced number of N-acetylgalactosamine (GalNAc) residues per HR and elevated relative abundance of IgA1 with three HR O-glycans were common features in IgAN patients; these features were associated with elevated blood pressure and reduced renal function. We speculate that the mechanisms underlying the reduced GalNAc content in IgA1 HR may be relevant to IgAN pathogenesis.
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Affiliation(s)
- Yukako Ohyama
- Department of Biomedical Molecular Sciences, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Hisateru Yamaguchi
- Department of Nursing, Yokkaichi Nursing and Medical Care University, Yokkaichi, Mie 512-8045, Japan
| | - Soshiro Ogata
- Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan
| | - Samantha Chiurlia
- University of Bari and Schena Foundation, Valenzano, Bari 70010, Italy
| | - Sharon N. Cox
- University of Bari and Schena Foundation, Valenzano, Bari 70010, Italy
| | - Nikoletta-Maria Kouri
- Department of Nephrology, Aristotle University of Thessaloniki, Thessaloniki, 54642, Greece
| | - Maria J. Stangou
- Department of Nephrology, Aristotle University of Thessaloniki, Thessaloniki, 54642, Greece
| | - Kazuki Nakajima
- Institute for Glyco-core Research, Gifu University, Gifu, Gifu 501-1193, Japan
| | - Hiroki Hayashi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Daijo Inaguma
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Midori Hasegawa
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Yukio Yuzawa
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Matthew B. Renfrow
- Departments of Biochemistry and Molecular Genetics and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jan Novak
- Departments of Biochemistry and Molecular Genetics and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | | | | | - Kazuo Takahashi
- Department of Biomedical Molecular Sciences, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
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Nagasawa Y, Misaki T, Ito S, Naka S, Wato K, Nomura R, Matsumoto-Nakano M, Nakano K. Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis. Int J Mol Sci 2022; 23:725. [PMID: 35054910 PMCID: PMC8775524 DOI: 10.3390/ijms23020725] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 12/23/2022] Open
Abstract
A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.
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Affiliation(s)
- Yasuyuki Nagasawa
- Department of General Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Hyogo, Japan
| | - Taro Misaki
- Division of Nephrology, Seirei Hamamatsu General Hospital, Hamamatsu 430-8558, Shizuoka, Japan;
- Department of Nursing, Faculty of Nursing, Seirei Christopher University, Hamamatsu 433-8558, Shizuoka, Japan
| | - Seigo Ito
- Department of Internal Medicine, Japan Self-Defense Gifu Hospital, Kakamigahara 502-0817, Gifu, Japan;
| | - Shuhei Naka
- Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Okayama, Japan; (S.N.); (M.M.-N.)
| | - Kaoruko Wato
- Department of Pediatric Dentistry, Division of Oral Infection and Disease Control, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (K.W.); (R.N.); (K.N.)
| | - Ryota Nomura
- Department of Pediatric Dentistry, Division of Oral Infection and Disease Control, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (K.W.); (R.N.); (K.N.)
| | - Michiyo Matsumoto-Nakano
- Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Okayama, Japan; (S.N.); (M.M.-N.)
| | - Kazuhiko Nakano
- Department of Pediatric Dentistry, Division of Oral Infection and Disease Control, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (K.W.); (R.N.); (K.N.)
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5
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Are there animal models of IgA nephropathy? Semin Immunopathol 2021; 43:639-648. [PMID: 34230994 DOI: 10.1007/s00281-021-00878-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 12/18/2022]
Abstract
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Up to 40% of IgAN patients develop end-stage kidney disease after 15-20 years. Despite the poor prognosis associated with this multifactorial disease, no clear treatment strategy has been identified, primarily due to the lack of understanding of its pathogenesis. Clinical observations indicate that aberrant IgAN immune systems, rather than intrinsic renal abnormalities, may be involved in its pathogenesis. Moreover, nephritogenic IgA and its related immune complexes are considered to be produced not only in the mucosa, but also in systemic immune sites, such as the bone marrow; however, there are numerous challenges to understanding this dynamic and complex immune axis in humans. Thus, several investigators have used experimental animal models. Although there are inter-strain differences in IgA molecules and immune responses between humans and rodents, animal models remain a powerful tool for investigating IgAN's pathogenesis, and the subsequent development of effective treatments. Here, we introduced some classical models of IgAN with or without genetic manipulation and recent translational approaches with some promising models. This includes humanized mouse models expressing human IgA1 and human IgA Fc receptor (CD89) that develops spontaneously the disease. Pre-clinical studies targeting IgA1 are discussed. Together, animal models are very useful tools to study pathophysiology and to validate new therapeutic approaches for IgAN.
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6
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Yamaji K, Suzuki Y, Suzuki H, Satake K, Horikoshi S, Novak J, Tomino Y. The kinetics of glomerular deposition of nephritogenic IgA. PLoS One 2014; 9:e113005. [PMID: 25409466 PMCID: PMC4237359 DOI: 10.1371/journal.pone.0113005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 10/17/2014] [Indexed: 11/18/2022] Open
Abstract
Whether IgA nephropathy is attributable to mesangial IgA is unclear as there is no correlation between intensity of deposits and extent of glomerular injury and no clear mechanism explaining how these mesangial deposits induce hematuria and subsequent proteinuria. This hinders the development of a specific therapy. Thus, precise events during deposition still remain clinical challenge to clarify. Since no study assessed induction of IgA nephropathy by nephritogenic IgA, we analyzed sequential events involving nephritogenic IgA from IgA nephropathy-prone mice by real-time imaging systems. Immunofluorescence and electron microscopy showed that serum IgA from susceptible mice had strong affinity to mesangial, subepithelial, and subendothelial lesions, with effacement/actin aggregation in podocytes and arcade formation in endothelial cells. The deposits disappeared 24-h after single IgA injection. The data were supported by a fluorescence molecular tomography system and real-time and 3D in vivo imaging. In vivo imaging showed that IgA from the susceptible mice began depositing along the glomerular capillary from 1 min and accumulated until 2-h on the first stick in a focal and segmental manner. The findings indicate that glomerular IgA depositions in IgAN may be expressed under the balance between deposition and clearance. Since nephritogenic IgA showed mesangial as well as focal and segmental deposition along the capillary with acute cellular activation, all glomerular cellular elements are a plausible target for injury such as hematuria.
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Affiliation(s)
- Kenji Yamaji
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Kenji Satake
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Satoshi Horikoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
- * E-mail:
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7
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Suzuki Y, Suzuki H, Makita Y, Takahata A, Takahashi K, Muto M, Sasaki Y, Kelimu A, Matsuzaki K, Yanagawa H, Okazaki K, Tomino Y. Diagnosis and activity assessment of immunoglobulin A nephropathy: current perspectives on noninvasive testing with aberrantly glycosylated immunoglobulin A-related biomarkers. Int J Nephrol Renovasc Dis 2014; 7:409-14. [PMID: 25378944 PMCID: PMC4219541 DOI: 10.2147/ijnrd.s50513] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Immunoglobulin (Ig) A nephropathy (IgAN) is the most common form of glomerular disease worldwide and is associated with a poor prognosis. Thus, development of a curative treatment and strategies for early diagnosis and treatment are urgently needed. Pathological analysis of renal biopsy is the gold standard for the diagnosis and assessment of disease activity; however, immediate and frequent assessment based on biopsy specimens is difficult. Therefore, a simple and safe alternative is desirable. On the other hand, it is now widely accepted that multi-hit steps, including production of aberrantly glycosylated serum IgA1 (first hit), and IgG or IgA autoantibodies that recognize glycan containing epitopes on glycosylated serum IgA1 (second hit) and their subsequent immune complex formation (third hit) and glomerular deposition (fourth hit), are required for continued progression of IgAN. Although the prognostic and predictive values of several markers have been discussed elsewhere, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of glycosylated serum IgA1 and related IgA immune complex. In addition, we confirmed a significant correlation between serum levels of these essential effector molecules and disease activity after treatment, suggesting that each can be considered as a practical surrogate marker of therapeutic effects in this slowly progressive disease. Such a noninvasive diagnostic and activity assessment method using these disease-oriented specific biomarkers may be useful in the early diagnosis of and intervention in IgAN, with appropriate indication for treatment, and thus aid in the future development and dissemination of specific and curative treatments.
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Affiliation(s)
- Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Hitoshi Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Yuko Makita
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Akiko Takahata
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Keiko Takahashi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Masahiro Muto
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Yohei Sasaki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Atikemu Kelimu
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | | | - Hiroyuki Yanagawa
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Keiko Okazaki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo
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8
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Aizawa M, Suzuki Y, Suzuki H, Pang H, Kihara M, Nakata J, Yamaji K, Horikoshi S, Tomino Y. Uncoupling of glomerular IgA deposition and disease progression in alymphoplasia mice with IgA nephropathy. PLoS One 2014; 9:e95365. [PMID: 24743510 PMCID: PMC3990643 DOI: 10.1371/journal.pone.0095365] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 03/25/2014] [Indexed: 11/18/2022] Open
Abstract
Previous clinical and experimental studies have indicated that cells responsible for IgA nephropathy (IgAN), at least in part, are localized in bone marrow (BM). Indeed, we have demonstrated that murine IgAN can be experimentally reconstituted by bone marrow transplantation (BMT) from IgAN prone mice in not only normal mice, but also in alymphoplasia mice (aly/aly) independent of IgA+ cells homing to mucosa or secondary lymphoid tissues. The objective of the present study was to further assess whether secondary lymph nodes (LN) contribute to the progression of this disease. BM cells from the several lines of IgAN prone mice were transplanted into aly/aly and wild-type mice (B6). Although the transplanted aly/aly showed the same degree of mesangial IgA and IgG deposition and the same serum elevation levels of IgA and IgA-IgG immune-complexes (IC) as B6, even in extent, the progression of glomerular injury was observed only in B6. This uncoupling in aly/aly was associated with a lack of CD4+ T cells and macrophage infiltration, although phlogogenic capacity to nephritogenic IC of renal resident cells was identical between both recipients. It is suggested that secondary LN may be required for the full progression of IgAN after nephritogenic IgA and IgA/IgG IC deposition.
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Affiliation(s)
- Masashi Aizawa
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Huihua Pang
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masao Kihara
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Junichiro Nakata
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kenji Yamaji
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Satoshi Horikoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
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9
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Kojima S, Koitabashi K, Iizuka N, Okamoto K, Arito M, Sato T, Kurokawa MS, Suematsu N, Shibagaki Y, Yasuda T, Kimura K, Kato T. Proteomic analysis of whole glomeruli in patients with IgA nephropathy using microsieving. Am J Nephrol 2014; 39:36-45. [PMID: 24434790 DOI: 10.1159/000357788] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 12/04/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND To promote understanding of immunoglobulin A nephropathy (IgAN) pathophysiology, we tried to elucidate glomerular protein profiles in IgAN, using microsieving that we established recently to isolate glomeruli from renal biopsy samples and proteomic approaches. METHODS Glomeruli were isolated from renal biopsy samples of patients with IgAN (n = 5) and with minimal change nephrotic syndrome (MCNS; n = 5) using microsieving. Proteins extracted from the isolated glomeruli were separated by 2-dimensional differential gel electrophoresis (2D-DIGE). Proteins with different amounts between the two groups were identified by mass spectrometry. One of the identified proteins, α-actinin-4 (ACTN4), was further analyzed by Western blotting, RT-polymerase chain reaction (PCR), and immunohistochemistry. RESULTS By 2D-DIGE, 72 out of the detected 1,170 protein spots showed significantly different intensity between the two groups (p < 0.05). Thirty-four out of the 72 protein spots showed more than 1.5-fold or less than 1/1.5-fold intensity, out of which 16 protein spots were successfully identified. No microbial protein was identified. ACTN4 molecules with a low molecular weight of approximately 77 kDa were found to increase in the IgAN group. Lack of an N-terminal part of ACTN4 was demonstrated by Western blotting. No defect of mRNA for ACTN4 was evidenced by RT-PCR. Predominant existence of ACTN4 in capillary walls of glomeruli of IgAN patients was demonstrated by immunohistochemistry in glomerular sections of patients with IgAN. CONCLUSION Use of microsieving enabled us to biochemically analyze glomerular proteins in renal biopsy samples from patients with glomerular diseases. With this method, we demonstrated skewed glomerular protein profiles in IgAN.
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Affiliation(s)
- Shigeki Kojima
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
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10
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Abstract
Since its first description in 1968, IgA nephropathy has remained the most common form of idiopathic glomerulonephritis leading to chronic kidney disease in developed countries. The exact pathogenesis of IgA nephropathy is still not well defined. Current data implicate an important genetic factor, especially in promoting the overproduction of an aberrant form of IgA1. The immunochemical aberrancy of IgA nephropathy is characterized by the undergalactosylation of O-glycans in the hinge region of IgA1. However, such aberrant glycosylation alone does not cause renal injury. The next stage of disease development requires the formation of glycan-specific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule. These antibodies often have reactivity against antigens from extrinsic microorganisms and might arise from recurrent mucosal infection. B cells that respond to mucosal infections, particularly tonsillitis, might produce the nephritogenic IgA1 molecule. With increased immune-complex formation and decreased clearance owing to reduced uptake by the liver, IgA1 binds to the glomerular mesangium via an as yet unidentified receptor. Glomerular IgA1 deposits trigger the local production of cytokines and growth factors, leading to the activation of mesangial cells and the complement system. Emerging data suggest that mesangial-derived mediators following glomerular deposition of IgA1 lead to podocyte and tubulointerstitial injury via mesangio-podocytic-tubular crosstalk. This Review summarizes the latest findings in the pathogenesis of IgA nephropathy.
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Affiliation(s)
- Kar Neng Lai
- Nephrology Center, 10th floor, Li Shu Pui Block, Hong Kong Sanatorium and Hospital, 2 Village Road, Happy Valley, Hong Kong.
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11
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Shi M, Liu ZW, Wang FS, Peruzzi L, Daprà V, Loiacono E, Vatrano S, Rollino C, Sepe V, Rampino T, Dal Canton A. Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin Exp Immunol 2011. [PMID: 21352202 DOI: 10.1111/j.1365-2249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multi-potent progenitor cells that are isolated from the bone marrow and several adult organs and tissues. These cells possess remarkable immunosuppressive properties and can inhibit the proliferation and function of the major immune cell populations, including T cells, B cells and natural killer (NK) cells; modulate the activities of dendritic cells (DCs); and induce regulatory T cells both in vivo and in vitro. These unique properties make MSCs ideal candidates for clinical application as immunosuppressants. The immunomodulatory effect of MSCs is mediated by a non-specific anti-proliferative action of these cells, which is dependent on cell-cell contact or secreted soluble factors such as indoleamine 2,3-dioxygenase (IDO), prostaglandin E(2) (PGE(2) ), nitric oxide (NO), histocompatibility leucocyte antigen-G (HLA-G), transforming growth factor (TGF)-β, interferon (IFN)-γ and interleukin (IL)-1β. Considerable progress has been obtained in preclinical studies on MSCs, including those on their ability to activate allogeneic cells. This review examines the current understanding of the immunomodulatory properties of MSCs and its therapeutic implication for immune-mediated diseases and transplant rejection.
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Affiliation(s)
- M Shi
- Beijing 302 Hospital, Beijing, China
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12
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Moriyama T, Nitta K. Tonsillectomy and Steroid Pulse Therapy for IgA Nephropathy. TOHOKU J EXP MED 2011; 224:243-50. [DOI: 10.1620/tjem.224.243] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Takahito Moriyama
- Department of Medicine, Kidney Center, Tokyo Women's Medical University
| | - Kosaku Nitta
- Department of Medicine, Kidney Center, Tokyo Women's Medical University
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13
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Coppo R, Camilla R, Amore A, Peruzzi L, Daprà V, Loiacono E, Vatrano S, Rollino C, Sepe V, Rampino T, Dal Canton A. Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin Exp Immunol 2009; 159:73-81. [PMID: 19891659 DOI: 10.1111/j.1365-2249.2009.04045.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
We investigated Toll-like receptors (TLR-3, -4 and -7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR-4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0.00200 and P = 0.0200). TLR-3 and TLR-7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR-4 expression (P = 0.0312). In a group of nephrotic syndromes, TLR-3, -4 and -7 expression was similar to healthy controls. A significant difference in TLR-4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1.73 m(2)/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0.5 g/1.73 m(2)/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up-regulation of TLR-4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.
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Affiliation(s)
- R Coppo
- Regina Margherita Children's Hospital, Torino, Italy.
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Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T, Kanou T, Tsukaguchi H, Novak J, Horikoshi S, Tomino Y. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol 2008; 19:2384-95. [PMID: 18776126 DOI: 10.1681/asn.2007121311] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Environmental pathogens are suspected to aggravate renal injury in IgA nephropathy (IgAN), but neither underlying mechanisms nor specific exogenous antigens have been identified. In this study, a genome-wide scan of ddY mice, which spontaneously develop IgAN, was performed, and myeloid differentiation factor 88 (MyD88) was identified as a candidate gene for progression of renal injury (chi(2) = 21.103, P = 0.00017). For evaluation of the potential influence of environmental pathogens on progression of renal injury, ddY mice were housed in either conventional or specific pathogen-free conditions. Expression of genes encoding toll-like receptors (TLR) and the signaling molecule MyD88 were quantified by real-time reverse transcription-PCR in splenocytes. Although the housing conditions did not affect the prevalence of IgAN, the severity of renal injuries was higher in the conventionally housed group. Mice that had IgAN and were housed in conventional conditions had higher levels of TLR9 and MyD88 transcripts than mice that had IgAN and were housed in specific pathogen-free conditions. Furthermore, nasal challenge with CpG-oligodeoxynucleotides, which are ligands for TLR9, aggravated renal injury, led to strong Th1 polarization, and increased serum and mesangial IgA. For investigation of whether these results may be generalizable to humans, single-nucleotide polymorphisms in the TLR9 and MyD88 genes were analyzed in two cohorts of patients with IgAN; an association was observed between TLR9 polymorphisms and disease progression. In summary, these findings suggest that activation of the TLR9/MyD88 pathway by common antigens may affect the severity of IgAN.
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Affiliation(s)
- Hitoshi Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
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