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1
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Zununi Vahed S, Hosseiniyan Khatibi SM, Ardalan M. Canonical effects of cytokines on glomerulonephritis: A new outlook in nephrology. Med Res Rev 2025; 45:144-163. [PMID: 39164945 DOI: 10.1002/med.22074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 08/28/2022] [Accepted: 08/04/2024] [Indexed: 08/22/2024]
Abstract
Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney-targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central "canonical effect" in the development of GN.
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Chugh SS, Clement LC. "Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end. Am J Physiol Renal Physiol 2023; 325:F685-F694. [PMID: 37795536 PMCID: PMC10878723 DOI: 10.1152/ajprenal.00219.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/11/2023] [Accepted: 10/02/2023] [Indexed: 10/06/2023] Open
Abstract
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
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Affiliation(s)
- Sumant S Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
| | - Lionel C Clement
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
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Li W, Shou X, Xiang W, He L, Li L, Fu H, Mao J. Urinary Sediment mRNA Level of CREBBP and CYBA in Children With Steroid-Resistant Nephrotic Syndrome. Front Immunol 2022; 12:801313. [PMID: 35173708 PMCID: PMC8841695 DOI: 10.3389/fimmu.2021.801313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/28/2021] [Indexed: 11/13/2022] Open
Abstract
BackgroundThis study aimed to evaluate gene expression patterns in urinary sediment samples of children with steroid-resistant nephrotic syndrome (SRNS).MethodsThe messenger RNA (mRNA) levels of 770 immune-related genes were detected using a NanoString nCounter platform. To verify the NanoString results, quantitative analysis of nine gene mRNAs was performed using real-time RT-PCR in more samples.ResultsFirstly, compared with the steroid-sensitive nephrotic syndrome (SSNS) group (n=3), significant changes were observed in the mRNA level of 70 genes, including MAP3K14, CYBA, SLC3A2, CREB-binding protein (CREBBP), CD68, forkhead box P1 (FOXP1), CD74, ITGB2, IFI30, and so forth, in the SRNS group (n=3). A total of 129 children with idiopathic nephrotic syndrome (INS), 15 with acute glomerulonephritis, and 6 with immunoglobulin A nephropathy (IgAN) were enrolled to verify the NanoString results. Compared with patients with IgAN, those with INS had significantly lower levels of FOXP1 (P=0.047) and higher levels of CREBBP (P=0.023). Among SSNS, the mRNA level of ITGB2 was significantly lower in the non-relapse group than in the non-frequent relapse and frequent-relapse groups (P=0.006). Compared with the SSNS group, CREBBP was significantly elevated in the SRNS group (P=0.02). Further, CYBA significantly decreased in the SRNS group (P=0.01). The area under the curve (AUC) for CREBBP and CYBA was 0.655 and 0.669, respectively. CREBBP had a sensitivity of 83.3% and a specificity of 49.4% and CYBA had a sensitivity of 58.3% and a specificity of 83.1% to rule out SSNS and SRNS. The diagnosis value was better for CREBBP+CYBA than for CREBBP or CYBA alone, indicating that the combination of CREBBP and CYBA was a more effective biomarker in predicting steroid resistance (AUC=0.666; sensitivity=63.9%; specificity=76.4%).ConclusionsThis study was novel in investigating the urinary sediment mRNA level in children with INS using high-throughput NanoString nCounter technology, and 70 genes that may relate to SRNS were found. The results revealed that the urinary sediment mRNA level of ITGB2 was significantly lower in the non-relapse group than in the non-frequent relapse and frequent-relapse groups. Meanwhile, CREBBP was significantly elevated and CYBA was significantly lowered in the SRNS group compared with the SSNS group.
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Affiliation(s)
- Wei Li
- Department of Clinical Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Xinyi Shou
- Department of Nephrology, The Children’ s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China
| | - Wenqing Xiang
- Department of Clinical Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Lin He
- Department of Clinical Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Lin Li
- Department of Clinical Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Haidong Fu
- Department of Nephrology, The Children’ s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China
| | - Jianhua Mao
- Department of Nephrology, The Children’ s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China
- *Correspondence: Jianhua Mao,
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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Renal Diseases Associated with Hematologic Malignancies and Thymoma in the Absence of Renal Monoclonal Immunoglobulin Deposits. Diagnostics (Basel) 2021; 11:diagnostics11040710. [PMID: 33921123 PMCID: PMC8071536 DOI: 10.3390/diagnostics11040710] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/02/2021] [Accepted: 04/13/2021] [Indexed: 12/05/2022] Open
Abstract
In addition to kidney diseases characterized by the precipitation and deposition of overproduced monoclonal immunoglobulin and kidney damage due to chemotherapy agents, a broad spectrum of renal lesions may be found in patients with hematologic malignancies. Glomerular diseases, in the form of paraneoplastic glomerulopathies and acute kidney injury with various degrees of proteinuria due to specific lymphomatous interstitial and/or glomerular infiltration, are two major renal complications observed in the lymphoid disorder setting. However, other hematologic neoplasms, including chronic lymphocytic leukemia, thymoma, myeloproliferative disorders, Castleman disease and hemophagocytic syndrome, have also been associated with the development of kidney lesions. These renal disorders require prompt recognition by the clinician, due to the need to implement specific treatment, depending on the chemotherapy regimen, to decrease the risk of subsequent chronic kidney disease. In the context of renal disease related to hematologic malignancies, renal biopsy remains crucial for accurate pathological diagnosis, with the aim of optimizing medical care for these patients. In this review, we provide an update on the epidemiology, clinical presentation, pathophysiological processes and diagnostic strategy for kidney diseases associated with hematologic malignancies outside the spectrum of monoclonal gammopathy of renal significance.
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Lee JM, Ko Y, Lee CH, Jeon N, Lee KH, Oh J, Kronbichler A, Saleem MA, Lim BJ, Shin JI. The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome. J Clin Med 2021; 10:jcm10030496. [PMID: 33535372 PMCID: PMC7866993 DOI: 10.3390/jcm10030496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 01/19/2023] Open
Abstract
Interleukin-4 (IL-4) expression is implicated in the pathogenesis of nephrotic syndrome (NS). This study aimed to investigate the changes in the transcriptomes of human podocytes induced by IL-4 treatment and to analyze whether these changes could be affected by simultaneous steroid treatment. Three groups of human podocytes were treated with control, IL-4, and IL-4 plus dexamethasone (DEX), respectively. We performed whole-transcriptome sequencing to identify differentially expressed genes (DEGs) between the groups. We investigated relevant biological pathways using Gene Ontology (GO) enrichment analyses. We also attempted to compare and validate the DEGs with the genes listed in PodNet, a literature-based database on mouse podocyte genes. A total of 176 genes were differentially expressed among the three groups. GO analyses showed that pathways related to cytoskeleton organization and cell signaling were significantly enriched. Among them, 24 genes were listed in PodNet, and 12 of them were previously reported to be associated with IL-4-induced changes in human podocytes. Of the 12 genes, the expression levels of BMP4, RARB, and PLCE1 were reversed when podocytes were simultaneously treated with DEX. In conclusion, this study explored changes in the transcriptome profiles of human podocytes treated with IL-4. Few genes were reported in previous studies and were previously validated in experiments with human podocytes. We speculate that IL-4 may exert pathogenic effects on the transcriptome of human podocytes, and a few genes may be involved in the pathogenesis.
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Affiliation(s)
- Jiwon M. Lee
- Department of Pediatrics, Chungnam National University Hospital and College of Medicine, Daejeon 35015, Korea;
| | - Younhee Ko
- Division of Biomedical Engineering, Hankuk University of Foreign Studies, Gyeonggi-do 17035, Korea;
| | - Chul Ho Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea; (C.H.L.); (K.H.L.)
- Division of Clinical Genetics, Severance Children’s Hospital, Seoul 03722, Korea
| | - Nara Jeon
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea; (C.H.L.); (K.H.L.)
| | - Jun Oh
- Department of Pediatrics, University Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria;
| | - Moin A. Saleem
- Children’s and Renal Unit and Bristol Renal, University of Bristol, Bristol BS2 8BJ, UK;
| | - Beom Jin Lim
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea;
- Correspondence: (B.J.L.); (J.I.S.)
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea; (C.H.L.); (K.H.L.)
- Division of Pediatric Nephrology, Severance Children’s Hospital, Seoul 03722, Korea
- Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: (B.J.L.); (J.I.S.)
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MicroRNAs as Biomarkers for Nephrotic Syndrome. Int J Mol Sci 2020; 22:ijms22010088. [PMID: 33374848 PMCID: PMC7795691 DOI: 10.3390/ijms22010088] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.
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Al Rushood M, Al-Eisa AA, Haider MZ. Interleukin-4 and Interleukin-13 Gene Polymorphisms in Children With Idiopathic Nephrotic Syndrome. Front Pediatr 2020; 8:591349. [PMID: 33330285 PMCID: PMC7710803 DOI: 10.3389/fped.2020.591349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/28/2020] [Indexed: 11/23/2022] Open
Abstract
Background: Idiopathic Nephrotic syndrome (INS) is an immune-mediated disease in which a number of cytokines, including IL-4 and IL-13, have been implicated in the pathogenesis. Cytokine gene polymorphisms might affect their levels and activity. Therefore, may affect INS susceptibility and response to treatment. The aim of the study was to determine the association of IL-4 and IL-13 gene polymorphisms and INS susceptibility and their effects on steroid responsiveness in children. Methods: The polymorphisms in IL-4 and IL-13 genes were detected by PCR-RFLP in 155 INS patients and 64 controls. Results: A total of 132 steroid-sensitive (SS) and 23 steroid resistance (SR) INS patients; mean age 7.3 ± 4.0 years, were included. Male: Female ratio was 2:1. No significant statistical differences were detected in the frequency of CC, CT, and TT genotypes of IL-4 gene compared to controls (P = 0.57, 0.61, and 1.00, respectively). There was no significant difference in the T and C-allele frequencies, in SS and SR subgroups. Analysis of IL-13 gene polymorphism also did not show significant statistical differences in the frequency of QQ, RQ, and RR genotypes compared to controls (P = 0.74, 1.00, and 0.68, respectively). No significant difference was found in the Q and R-allele frequency. However, the heterozygous RQ genotype of the IL13 gene was significantly higher in SS INS patients compared to the SR INS cases (P = 0.04). Conclusion: Our findings did not show an association between IL-4 and IL-13 gene polymorphisms and INS susceptibility. However, IL-13 RQ genotype was expressed more in children with INS who are steroid sensitive.
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Affiliation(s)
- Maysoun Al Rushood
- Department of Pediatrics, Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait City, Kuwait
| | - Amal A Al-Eisa
- Department of Pediatrics, Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait City, Kuwait
| | - Mohammad Z Haider
- Department of Pediatrics, Faculty of Medicine, Health Sciences Center, Kuwait University, Kuwait City, Kuwait
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Kim AH, Chung JJ, Akilesh S, Koziell A, Jain S, Hodgin JB, Miller MJ, Stappenbeck TS, Miner JH, Shaw AS. B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2017; 2:81836. [PMID: 29093269 DOI: 10.1172/jci.insight.81836] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 10/05/2017] [Indexed: 12/13/2022] Open
Abstract
The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. This effect was mediated by IL-4, as transfer of IL-4-deficient B cells did not induce proteinuria. Overexpression of IL-4 in mice was sufficient to induce kidney injury and proteinuria and could be attenuated by JAK kinase inhibitors. Since IL-4 is a specific activator of STAT6, we analyzed kidney biopsies and demonstrated STAT6 activation in up to 1 of 3 of minimal change disease patients, suggesting IL-4 or IL-13 exposure in these patients. These data suggest that the role of B cells in nephrotic syndrome could be mediated by cytokines.
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Affiliation(s)
- Alfred Hj Kim
- Division of Rheumatology, Department of Internal Medicine, and
| | - Jun-Jae Chung
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Shreeram Akilesh
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ania Koziell
- Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London and Department of Paediatric Nephrology, Evelina Children's Hospital, London, United Kingdom
| | - Sanjay Jain
- Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Mark J Miller
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Thaddeus S Stappenbeck
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jeffrey H Miner
- Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Andrey S Shaw
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.,Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, USA
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Rochman M, Travers J, Abonia JP, Caldwell JM, Rothenberg ME. Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity. JCI Insight 2017; 2:96789. [PMID: 29046486 DOI: 10.1172/jci.insight.96789] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 09/11/2017] [Indexed: 12/31/2022] Open
Abstract
Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus mediated by an IL-13-driven epithelial cell transcriptional program. Herein, we show that the cytoskeletal protein synaptopodin (SYNPO), previously associated with podocytes, is constitutively expressed in esophageal epithelium and induced during allergic inflammation. In addition, we show that the SYNPO gene is transcriptionally and epigenetically regulated by IL-13 in esophageal epithelial cells. SYNPO was expressed in the basal layer of homeostatic esophageal epithelium, colocalized with actin filaments, and expanded into the suprabasal epithelium in EoE patients, where expression was elevated 25-fold compared with control individuals. The expression level of SYNPO in esophageal biopsies correlated with esophageal eosinophil density and was improved following anti-IL-13 treatment in EoE patients. In esophageal epithelial cells, SYNPO gene silencing reduced epithelial motility in a wound healing model, whereas SYNPO overexpression impaired epithelial barrier integrity and reduced esophageal differentiation. Taken together, we demonstrate that SYNPO is induced by IL-13 in vitro and in vivo, is a nonredundant regulator of epithelial cell barrier function and motility, and is likely involved in EoE pathogenesis.
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Analysis of T Cell Subsets in Adult Primary/Idiopathic Minimal Change Disease: A Pilot Study. Int J Nephrol 2017; 2017:3095425. [PMID: 28894608 PMCID: PMC5574215 DOI: 10.1155/2017/3095425] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/15/2017] [Accepted: 06/14/2017] [Indexed: 12/16/2022] Open
Abstract
AIM To characterise infiltrating T cells in kidneys and circulating lymphocyte subsets of adult patients with primary/idiopathic minimal change disease. METHODS In a cohort of 9 adult patients with primary/idiopathic minimal change recruited consecutively at disease onset, we characterized (1) infiltrating immune cells in the kidneys using immunohistochemistry and (2) circulating lymphocyte subsets using flow cytometry. As an exploratory analysis, association of the numbers and percentages of both kidney-infiltrating immune cells and the circulating lymphocyte subsets with kidney outcomes including deterioration of kidney function and proteinuria, as well as time to complete clinical remission up to 48 months of follow-up, was investigated. RESULTS In the recruited patients with primary/idiopathic minimal change disease, we observed (a) a dominance of infiltrating T helper 17 cells and cytotoxic cells, comprising cytotoxic T cells and natural killer cells, over Foxp3+ Treg cells in the renal interstitium; (b) an increase in the circulating total CD8+ T cells in peripheral blood; and (c) an association of some of these parameters with kidney function and proteinuria. CONCLUSIONS In primary/idiopathic minimal change disease, a relative numerical dominance of effector over regulatory T cells can be observed in kidney tissue and peripheral blood. However, larger confirmatory studies are necessary.
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Uwaezuoke SN. The role of novel biomarkers in childhood idiopathic nephrotic syndrome: a narrative review of published evidence. Int J Nephrol Renovasc Dis 2017; 10:123-128. [PMID: 28615961 PMCID: PMC5459980 DOI: 10.2147/ijnrd.s131869] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Two histological subtypes of idiopathic nephrotic syndrome are commonly recognized in children, namely minimal change nephropathy and focal segmental glomerulosclerosis. Children with minimal change nephropathy (the majority of whom are steroid-sensitive) and focal segmental glomerulosclerosis (the majority of whom are steroid-resistant) require early identification in order to ensure appropriate therapeutic intervention and better outcome. Although renal biopsy and histology remain the ideal diagnostic steps to identify these histological subtypes, reports indicate that serum and urinary biomarkers are now being utilized in the investigation of childhood idiopathic nephrotic syndrome. This paper aims to review the diagnostic and prognostic utility of novel biomarkers in childhood idiopathic nephrotic syndrome and to highlight their role in differentiating steroid-sensitive nephrotic syndrome (SRNS) from steroid-resistant nephrotic syndrome (SSNS). Using the terms "idiopathic nephrotic syndrome," "children," and "biomarkers" the PubMed database was searched for relevant studies related to the topic. Biomarkers such as adiponectin, neopterin, β2-microglobulin, and N-acetyl-β-D glucosaminidase were reported as diagnostic markers. In addition to neopterin and N-acetyl-β-D glucosaminidase, urine vitamin D-binding protein and α1β-glycoprotein were shown to differentiate SRNS from SSNS while N-acetyl-β-D glucosaminidase and β2-microglobulin could predict steroid responsiveness and renal outcome in SRNS. Although progress has been made in demonstrating the diagnostic and prognostic utility of these biomarkers, their limited availability in most laboratories has precluded a complete paradigm shift from the conventional renal biopsy. Nevertheless, further longitudinal studies are required to establish their usefulness as noninvasive predictors of disease response to immunosuppressive therapy.
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Affiliation(s)
- Samuel N Uwaezuoke
- Department of Pediatrics, Pediatric Nephrology Firm, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria
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Madanchi N, Bitzan M, Takano T. Rituximab in Minimal Change Disease: Mechanisms of Action and Hypotheses for Future Studies. Can J Kidney Health Dis 2017; 4:2054358117698667. [PMID: 28540057 PMCID: PMC5433659 DOI: 10.1177/2054358117698667] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 11/23/2016] [Indexed: 12/13/2022] Open
Abstract
Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD). MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.
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Affiliation(s)
- Nima Madanchi
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Martin Bitzan
- Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Tomoko Takano
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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15
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Uwaezuoke SN. Steroid-sensitive nephrotic syndrome in children: triggers of relapse and evolving hypotheses on pathogenesis. Ital J Pediatr 2015; 41:19. [PMID: 25888239 PMCID: PMC4379699 DOI: 10.1186/s13052-015-0123-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 03/04/2015] [Indexed: 01/09/2023] Open
Abstract
Nephrotic syndrome remains the most common manifestation of glomerular disease in childhood. Minimal change nephropathy is the most common cause of the syndrome in children. Despite its initial high response rate to corticosteroids and its favorable prognosis, relapses are common leading to increased morbidity and cost of treatment.This review seeks to appraise the common triggers of relapse and to highlight the evolving hypotheses about the pathogenesis of the syndrome. Literature search was conducted through PubMed, Google web search and Cochrane Database of Systematic reviews using relevant search terms.Acute respiratory infections and urinary tract infections are the most frequent infectious triggers of relapse. Targeted interventions like initiating corticosteroid or its dose-adjustment during episodes of acute respiratory infection and zinc supplementation are reportedly effective in reducing relapse rates. Hypotheses on pathogenesis of the syndrome have evolved from the concepts of 'immune dysregulation', 'increased glomerular permeability' to 'podocytopathy'.Although development of drugs which can regulate the pathways for podocyte injury offers future hope for effective and targeted treatment, the relapse-specific interventions currently contribute to significant reduction in disease morbidity.
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Affiliation(s)
- Samuel N Uwaezuoke
- Department of Paediatric Nephrology Unit, University of Nigeria Teaching Hospital, Postal code- 400001, Ituku-Ozalla, Enugu, Enugu State, Nigeria.
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Park SJ, Saleem MA, Nam JA, Ha TS, Shin JI. Effects of interleukin-13 and montelukast on the expression of zonula occludens-1 in human podocytes. Yonsei Med J 2015; 56:426-32. [PMID: 25683991 PMCID: PMC4329354 DOI: 10.3349/ymj.2015.56.2.426] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE The aim of this study was to investigate whether pathologic changes in zonula occludens-1 (ZO-1) are induced by interleukin-13 (IL-13) in the experimental minimal-change nephrotic syndrome (MCNS) model and to determine whether montelukast, a leukotriene receptor antagonist, has an effect on ZO-1 restoration in cultured human podocytes. MATERIALS AND METHODS Human podocytes cultured on bovine serum albumin-coated plates were treated with different doses of IL-13 and montelukast and then examined for distribution using confocal microscopy and for ZO-1 protein levels using Western blotting. RESULTS ZO-1 was internalized and shown to accumulate in the cytoplasm of human podocytes in an IL-13 dose-dependent manner. High doses (50 and 100 ng/mL) of IL-13 decreased the levels of ZO-1 protein at 12 and 24 h (both p<0.01; n=3), which were significantly reversed by a high dose (0.5 μM) montelukast treatment (p<0.01; n=3). CONCLUSION Our results suggest that IL-13 alters the expression of ZO-1, and such alterations in the content and distribution of ZO-1 may be relevant in the pathogenesis of proteinuria in the MCNS model.
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Affiliation(s)
- Se Jin Park
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea.; Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Moin A Saleem
- Children's and Academic Renal Unit, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Ja-Ae Nam
- Department of Pediatrics, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Tae-Sun Ha
- Department of Pediatrics, Chungbuk National University College of Medicine, Cheongju, Korea.
| | - Jae Il Shin
- Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Protection Effect of Zhen-Wu-Tang on Adriamycin-Induced Nephrotic Syndrome via Inhibiting Oxidative Lesions and Inflammation Damage. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:131604. [PMID: 24812565 PMCID: PMC4000650 DOI: 10.1155/2014/131604] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Revised: 02/23/2014] [Accepted: 02/24/2014] [Indexed: 01/11/2023]
Abstract
Zhen-wu-tang (ZWT), a well-known formula in China, is widely used to treat chronic kidney diseases. However, very little information on ZWT's mechanism of action is currently available. In this study, we investigated the possible protective role and underlying mechanism of ZWT on nephrotic syndrome (NS) induced by Adriamycin (intravenous injection, 6.0 mg/kg) in rats using biochemical and histopathological approaches. ZWT decreased urine protein excretion and the serum levels of total cholesterol, triglycerides, blood urea nitrogen, and creatinine significantly in diseased rats. A decrease in plasma levels of total protein and albumin was also recorded in nephropathic rats. Pathological results show an improved pathological state and recovering glomerular structure in ZWT treatment groups. ZWT decreased renal IL-8 level but increased renal IL-4 level. In addition, rats subjected to ZWT exhibited less IgG deposition in glomerulus compared with model group. RT-PCR results showed that ZWT decreased the mRNA expression of NF- κ B p65 and increased the mRNA expression of I κ B. Furthermore, ZWT reduced the level of MDA and increased SOD activity. These results demonstrated that ZWT ameliorated Adriamycin-induced NS in rats possibly by inhibiting Adriamycin-induced inflammation damage, enhancing body's antioxidant capacity, thereby protecting glomerulus from injury.
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Sahali D, Sendeyo K, Mangier M, Audard V, Zhang SY, Lang P, Ollero M, Pawlak A. Immunopathogenesis of idiopathic nephrotic syndrome with relapse. Semin Immunopathol 2014; 36:421-9. [PMID: 24402710 DOI: 10.1007/s00281-013-0415-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 12/03/2013] [Indexed: 12/14/2022]
Abstract
Idiopathic change nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults, is characterized by heavy proteinuria and a relapsing remitting course. Although the mechanisms underlying the pathophysiology of proteinuria remain unclear, clinical and experimental observations suggest that lymphocyte and podocyte disturbances are two sides of the disease. The current hypothesis suggests that immune cells release a putative factor, which alters podocyte function resulting in nephrotic proteinuria. Besides T-cell abnormalities, recent evidence of B-cell depletion efficacy in sustained remissions added a new challenge in understanding the immunological mechanisms of INS. In this review, we discuss recent insights related to podocyte disorders occurring in INS and their relevance in human diseases.
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Affiliation(s)
- Djillali Sahali
- Service de Néphrologie et Transplantation, AP-HP, CHU Henri Mondor, Creteil, 94010, France,
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Srivastava T, Sharma M, Yew KH, Sharma R, Duncan RS, Saleem MA, McCarthy ET, Kats A, Cudmore PA, Alon US, Harrison CJ. LPS and PAN-induced podocyte injury in an in vitro model of minimal change disease: changes in TLR profile. J Cell Commun Signal 2012; 7:49-60. [PMID: 23161414 DOI: 10.1007/s12079-012-0184-0] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 11/06/2012] [Indexed: 12/12/2022] Open
Abstract
Minimal change disease (MCD), the most common idiopathic nephrotic syndrome in children, is characterized by proteinuria and loss of glomerular visceral epithelial cell (podocyte) ultrastructure. Lipopolysaccharide (LPS) and puromycin aminonucleoside (PAN) are used to study podocyte injury in models of MCD in vivo and in vitro. We hypothesized that LPS and PAN influence components of the innate immune system in podocytes such as the Toll-Like Receptor (TLRs), TLR adapter molecules, and associated cytokines. Our results show that cultured human podocytes constitutively express TLRs 1-6 and TLR-10, but not TLRs 7-9. LPS (25 μg/ml) or PAN (60 μg/ml) caused comparable derangement of the actin cytoskeleton in podocytes. Quantitative RT-PCR analysis show that LPS differentially up-regulated the expression of genes for TLRs (1 > 4 ≥ 2 > 3 > 6 > 5), the adapter molecule, MyD88, and transcription factor NF-κB within one hour. LPS also caused increased levels of IL-6, IL-8 and MCP1 without exerting any effect on TNF-α, IFN-α or TGF-β1 at 24 h. Immunofluorescence intensity analysis of confocal microscopy images showed that LPS induced a significant increase in nuclear translocation of NF-κB by 6 h. In contrast, PAN-induced only small changes in the expression of TLRs 2-6 that included a persistent increase in TLRs 2 and 5, a transient increase in TLR-4, and a gradual increase in TLRs 3 and 6 between 1 and 6 h. Correspondingly, it did not alter pro-inflammatory cytokine levels in podocytes. However, PAN induced a low but significant increase in NF-κB nuclear translocation within one hour that remained unchanged up to 6 h. In summary, these novel findings show that LPS, a known TLR-4 ligand, induced the gene expression of multiple TLRs with maximum effect on the expression of TLR-1 suggesting a loss of receptor selectivity and induction of receptor interactions in podocytes. A comparable derangement of the podocyte cytoskeleton and significant increase in the nuclear translocation of NF-κB by PAN suggest that disparate but complementary mechanisms may contribute to the development of podocytopathy in MCD.
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Affiliation(s)
- Tarak Srivastava
- Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA
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Youn YS, Lim HH, Lee JH. The clinical characteristics of steroid responsive nephrotic syndrome of children according to the serum immunoglobulin E levels and cytokines. Yonsei Med J 2012; 53:715-22. [PMID: 22665336 PMCID: PMC3381495 DOI: 10.3349/ymj.2012.53.4.715] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
PURPOSE The nephrotic syndrome (NS) is characterized by the favorable response to glucocorticoid therapy and the development of NS may be associated with dysfunctional immune systems. In order to investigate the serum immunoglobulin E (IgE) levels and cytokines activity in pediatric NS, the total of 32 steroid responsive NS patients and 5 healthy controls were enrolled in this study. MATERIALS AND METHODS All patients were divided into two groups according to the initial serum IgE levels, such as normal and high IgE group, and their clinical characteristics were evaluated. In addition, serum levels of interleukin (IL)-4, IL-5, IL-10 and transforming growth factor (TGF)-β were compared and correlated with serum albumin, proteinuria by means of disease severity, and cytokines. RESULTS In the high IgE group, the higher comorbidity of allergic diseases and relapsing rate, the longer duration of steroid therapy before initial remission, and the higher serum IL-4 and IL-5 levels were found. In all patients, initially higher serum levels of IL-4 and IL-5 declined to normal levels after steroid therapy, whereas the serum IL-10 levels showed no significant difference between nephrotic phase (heavy proteinuria) and remission phase (no proteinuria) of NS. The serum TGF-β levels of the nephrotic phase were significantly lower than those of remission phase or control group, and returned to normal control levels after steroid therapy. CONCLUSION This study indicates that initial IgE level is associated with steroid responsiveness and disease severity, and cytokine activities may also be related to the pathogenesis of pediatric steroid responsive NS.
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Affiliation(s)
- You Sook Youn
- Department of Pediatrics, Deajeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Korea
| | - Han Hyuk Lim
- Department of Pediatrics, Chungnam National University School of Medicine, Daejeon, Korea
| | - Jae Ho Lee
- Department of Pediatrics, Chungnam National University School of Medicine, Daejeon, Korea
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Cyprinus carpio Decoction Improves Nutrition and Immunity and Reduces Proteinuria through Nephrin and CD2AP Expressions in Rats with Adriamycin-Induced Nephropathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:237482. [PMID: 22675377 PMCID: PMC3362917 DOI: 10.1155/2012/237482] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Revised: 03/03/2012] [Accepted: 03/19/2012] [Indexed: 11/18/2022]
Abstract
Cyprinus carpio decoction (CCD) is a well-known Chinese food medicine formula, accepted widely as a useful therapy in preventing edema and proteinuria caused by renal disease. However, the mechanism underlying this effect remains unclear. The current study investigated the potential mechanism of CCD in alleviating nephropathy induced by adriamycin (ADR) in rats. 70 eight-week-old Wistar rats were randomly divided into normal, model, fosinopril, YD, YG groups. All rats except for the normal group received 6.5 mg/kg·bw of ADR injection into the vena caudalis once. Different doses of CCD (11.3 and 22.5 g kg(-1)) were lavaged to rats in YD and YG groups, respectively. Then the serum biochemical values of the total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (Cr), electrolyte levels, and the urinary protein (UP) content in 12 hr urine were measured. Interleukin-4 (IL-4) and interferon (INF-γ) were measured by enzyme-like immunosorbent assay (ELISA). The pathomorphological analysis was observed using light and electron microscopy, and the expressions of nephrin and CD2-associated protein (CD2AP) in renal tissues were determined by immunohistochemical assay. The results indicated that CCD can relieve ADR-induced nephropathy (ADN) by improving the nutrition status, regulating the immunity, and inhibiting proteinuria by increasing nephrin and CD2AP expressions.
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Couser WG. Basic and translational concepts of immune-mediated glomerular diseases. J Am Soc Nephrol 2012; 23:381-99. [PMID: 22282593 DOI: 10.1681/asn.2011030304] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Genetically modified immune responses to infections and self-antigens initiate most forms of GN by generating pathogen- and danger-associated molecular patterns that stimulate Toll-like receptors and complement. These innate immune responses activate circulating monocytes and resident glomerular cells to release inflammatory mediators and initiate adaptive, antigen-specific immune responses that collectively damage glomerular structures. CD4 T cells are needed for B cell-driven antibody production that leads to immune complex formation in glomeruli, complement activation, and injury induced by both circulating inflammatory and resident glomerular effector cells. Th17 cells can also induce glomerular injury directly. In this review, information derived from studies in vitro, well characterized experimental models, and humans summarize and update likely pathogenic mechanisms involved in human diseases presenting as nephritis (postinfectious GN, IgA nephropathy, antiglomerular basement membrane and antineutrophil cytoplasmic antibody-mediated crescentic GN, lupus nephritis, type I membranoproliferative GN), and nephrotic syndrome (minimal change/FSGS, membranous nephropathy, and C3 glomerulopathies). Advances in understanding the immunopathogenesis of each of these entities offer many opportunities for future therapeutic interventions.
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Affiliation(s)
- William G Couser
- Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
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Ishimoto T, Shimada M, Araya CE, Huskey J, Garin EH, Johnson RJ. Minimal change disease: a CD80 podocytopathy? Semin Nephrol 2011; 31:320-5. [PMID: 21839364 DOI: 10.1016/j.semnephrol.2011.06.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Minimal change disease is the most common nephrotic syndrome in children. Although the etiology of minimal change disease remains to be elucidated, it has been postulated that it is the result of a circulating T-cell factor that causes podocyte cytoskeleton disorganization leading to increased glomerular capillary permeability and/or changes in glomerular basement membrane heparan sulfate glycosaminoglycans resulting in proteinuria. Minimal change disease has been associated with allergies and Hodgkin disease. Consistent with these associations, a role for interleukin-13 with minimal change disease has been proposed. Furthermore, studies evaluating podocytes also have evolved. Recently, increased expression of CD80 (also termed B7-1) on podocytes was identified as a mechanism for proteinuria. CD80 is inhibited by binding to CTLA-4, which is expressed on regulatory T cells. Recently, we showed that urinary CD80 is increased in minimal change disease patients and limited studies have suggested that it is not commonly present in the urine of patients with other glomerular diseases. Interleukin-13 or microbial products via Toll-like receptors could be factors that induce CD80 expression on podocytes. CTLA-4 appears to regulate CD80 expression in podocytes, and to be altered in minimal change disease patients. These findings lead us to suggest that proteinuria in minimal change disease is caused by persistent CD80 expression in podocytes, possibly initiated by stimulation of these cells by antigens or cytokines.
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Affiliation(s)
- Takuji Ishimoto
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA.
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Abstract
The development of proliferative podocytopathies has been linked to ligation of tumor necrosis factor receptor 2 (TNFR2) expressed on the renal parenchyma; however, the TNFR2-positive cells within the kidney responsible for podocyte injury are unknown. We detected de novo expression of TNFR2 on podocytes before hyperplastic injury in crescentic glomerulonephritis of mice with nephrotoxic nephritis, and in collapsing glomerulopathy of Tg26(HIV/nl) mice, kd/kd mice, and human beings. We further found that serum levels of soluble TNF-α and TNFR2 correlated significantly with renal injury in Tg26(HIV/nl) mice. Thus, we asked whether ligand binding of TNFR2 on podocytes ex vivo precipitates the characteristic proliferative and pro-inflammatory diseased podocyte phenotypes. Soluble TNF-α activated NF-κB and dose-dependently induced podocyte proliferation, marked by the expression of the podocyte G(1) cyclin and NF-κB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-κB signature, and activated podocytes secreting CCL2- and CCL5-induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-κB activation and the induction of cyclin D1 by TNF-α, and identified TNFR2 as the primary receptor that induced IκBα degradation, the initiating event in NF-κB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-κB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-α, in the absence of other TNFR2-positive renal cell types in proliferative podocytopathies.
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Le Berre L, Bruneau S, Renaudin K, Naulet J, Usal C, Smit H, Soulillou JP, Dantal J. Development of initial idiopathic nephrotic syndrome and post-transplantation recurrence: evidence of the same biological entity. Nephrol Dial Transplant 2010; 26:1523-32. [PMID: 20935016 DOI: 10.1093/ndt/gfq597] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Buffalo/Mna rats spontaneously develop a nephrotic syndrome (NS). We have demonstrated that this rat nephropathy recurs after renal transplantation. We studied this recurrence by kinetic analysis of graft lesions, infiltrating cells and cytokines. METHODS Kidneys from LEW.1 W rats were grafted into proteinuric Buff/Mna or healthy Wistar Furth recipients. Kidney samples were harvested before, during and after the occurrence of proteinuria and analysed for renal histology, cell populations and cytokine transcripts. Results were compared with the evolution of the initial disease studied previously. RESULTS Both groups showed normal graft histology at Day 7 and an increasing podocyte swelling at Day 45 was seen only in the Buff/Mna recipients. At Day 80, glomerular atrophy with podocytosis and focal segmental glomerular sclerosis lesions, accompanied by tubular dilatation, appeared in the Buff/Mna group. At Day 122, the intensity of the tubular and glomerular lesions increased in Buff/Mna recipients but not in the control group. An analysis of desmin and Kim-1 (early markers of glomerular and tubular damage, respectively) transcripts expression showed that glomerular lesions precede tubular injury in this model. A monocyte infiltration associated with an increase in TNFα, IL1 and IL12 transcripts appeared before the recurrence. An early increase in Cbeta TCR transcripts with a predominant Th2 profile was observed, highlighting a Th2 polarization in the Buff/Mna recurrence. CONCLUSIONS The comparison of profiles of recurrence and initial disease highlighted the same mediators for both events. We propose that initial Buff/Mna idiopathic nephrotic syndrome (INS) and post-transplantation recurrence represent the same entity and a valuable tool for the study of recurring INS.
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Loymans RJB, Berend K, Abreu de Martinez VG, Florquin S, de Vries APJ. Nephrotic syndrome in Kimura's disease: apropos a case of the glomerular tip lesion in an African-Caribbean male. NDT Plus 2010; 4:60-2. [PMID: 25984106 PMCID: PMC4421622 DOI: 10.1093/ndtplus/sfq167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 09/03/2010] [Accepted: 09/06/2010] [Indexed: 11/13/2022] Open
Affiliation(s)
- Rik J B Loymans
- Department of Medicine , St. Elisabeth Hospital , Breedestraat 193 (O), Willemstad, Curacao , The Netherlands Antilles ; Department of General Practice, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Kenrick Berend
- Department of Medicine , St. Elisabeth Hospital , Breedestraat 193 (O), Willemstad, Curacao , The Netherlands Antilles
| | - Victoria G Abreu de Martinez
- Department of Pathology , St. Elisabeth Hospital , Breedestraat 193 (O), Willemstad, Curacao , The Netherlands Antilles
| | - Sandrine Florquin
- Department of Pathology, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Aiko P J de Vries
- Department of Medicine , St. Elisabeth Hospital , Breedestraat 193 (O), Willemstad, Curacao , The Netherlands Antilles ; Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Centre , Leiden University , Leiden , The Netherlands
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Ito Y, Goldschmeding R, Kasuga H, Claessen N, Nakayama M, Yuzawa Y, Sawai A, Matsuo S, Weening JJ, Aten J. Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis. Am J Physiol Renal Physiol 2010; 299:F545-58. [PMID: 20576680 DOI: 10.1152/ajprenal.00120.2009] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Transforming growth factor (TGF)-beta(1), -beta(2), and -beta(3) are involved in control of wound repair and development of fibrosis. Connective tissue growth factor (CTGF) expression is stimulated by all TGF-beta isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGF-beta(1) or to facilitate interaction of TGF-beta(1) with its receptor, but its interactions with TGF-beta isoforms in nonpathological conditions are unexplored so far. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGF-beta, we compared expression patterns of CTGF and TGF-beta isoforms in rat and human glomerulogenesis and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the comma- and S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGF-beta(1), -beta(2), and -beta(3) protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGF-beta(2) and -beta(3) protein, and in the absence of TGF-beta(1), CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGF-beta(1) and CTGF were again coexpressed, often with TGF-beta(2) and -beta(3), in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy (IgA NP). Coordinated expression of TGF-beta isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGF-beta(1) and CTGF is associated with development of severe glomerulonephritis and glomerulosclerosis.
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Affiliation(s)
- Yasuhiko Ito
- Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands
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Abstract
Remarkable advances have been made in the past decade in understanding the pathophysiology of idiopathic nephrotic syndrome. Although the initiating events leading to the onset of proteinuria still are not well defined, it has become increasingly clear that many glomerular diseases can be classified as podocytopathies, with injury to the podocyte playing a major role in the development and progression of disease. A complex interaction of immune system mediators, slit diaphragm signal transduction, podocyte injury and conformational change, and mediators of apoptosis and fibrosis determine the extent and nature of proteinuria and progression of glomerulosclerosis. New insights into the pathogenesis of idiopathic nephrotic syndrome likely will lead to innovative therapies and new approaches to management and prevention.
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Efficacy of zinc supplements in reducing relapses in steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2009; 24:1583-6. [PMID: 19347367 DOI: 10.1007/s00467-009-1170-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Revised: 02/24/2009] [Accepted: 02/27/2009] [Indexed: 12/15/2022]
Abstract
Relapses in steroid-sensitive nephrotic syndrome (SSNS) often follow infections of the respiratory or gastrointestinal tract. Based on data that zinc supplements reduce the risk of infections, we examined the efficacy of such supplements in reducing relapse rates in these patients. Eighty-one patients with SSNS (1-16 years old) were stratified into frequent (n = 52) and infrequent (n = 29) relapsers and randomized to receive 12-months of therapy with the recommended dietary allowance of zinc (10 mg/day) (n = 40) or placebo (n = 41). Patients with frequent relapses also received long-term, alternate-day prednisolone. Subjects receiving zinc showed a 20% lower frequency of relapses, with 44.7% of the patients having sustained remission compared to 27.5% in the placebo group (P > 0.05). Patients with frequent relapses receiving zinc showed a 28% reduction in relapse rates and a significantly higher likelihood of sustained remission (P = 0.02). Findings from this double blind, randomized study suggest that zinc supplementation results in trends towards remission and reduced relapses, especially in patients with frequent relapses. Prospective, adequately powered studies are required for confirmation of these findings.
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Polymorphisms in interleukin-4-related genes in patients with minimal change nephrotic syndrome. Pediatr Nephrol 2009; 24:489-95. [PMID: 19011907 DOI: 10.1007/s00467-008-1003-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Revised: 07/14/2008] [Accepted: 08/05/2008] [Indexed: 10/21/2022]
Abstract
Minimal change nephrotic syndrome (MCNS) in children is frequently associated with allergy and immunoglobulin E production. T helper subtype 2 cytokines, such as interleukin (IL)-4 and IL-13, may have an important role in the development of atopy. We investigated the association of genetic variations of IL-4 receptor alpha chain (IL-4Ralpha), IL-13 and signal transducer and activator of transcription 6 (STAT6) genes with MCNS. We analyzed these polymorphisms in 85 Japanese children (55 males, 30 females) with MCNS and 127 healthy controls with neither allergic nor renal diseases. Genomic DNA was extracted from peripheral blood leukocytes. The single nucleotide polymorphisms of IL-4Ralpha (Ile50Val) and IL-13 (R130Q) were detected by primer-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism analysis, respectively. GT repeat polymorphism in STAT6 gene exon 1 was investigated by fragment length analysis. A significant difference in allelic frequencies in the STAT6 gene was detected between the MCNS and control groups. There was no significant difference between the two groups for genetic variations of IL-4Ralpha and IL-13 genes. We found a significant difference in IL-4Ralpha gene polymorphism between MCNS subgroups divided according to the number of relapses. These results suggested that the genetic variation in the first exon of the STAT6 gene may be associated with a predisposition to MCNS and that the genetic variation in the IL-4Ralpha gene may be associated with its clinical course.
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Al-Sadi R, Boivin M, Ma T. Mechanism of cytokine modulation of epithelial tight junction barrier. Front Biosci (Landmark Ed) 2009; 14:2765-78. [PMID: 19273235 DOI: 10.2741/3413] [Citation(s) in RCA: 456] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cytokines play a crucial role in the modulation of inflammatory response in the gastrointestinal tract. Pro-inflammatory cytokines including tumor necrosis factor-alpha, interferon-gamma, interleukin-1beta?IL-1beta?, and interleukin-12 are essential in mediating the inflammatory response, while anti-inflammatory cytokines including interleukin-10 and transforming growth factor-beta are important in the attenuation or containment of inflammatory process. It is increasingly recognized that cytokines have an important physiological and pathological effect on intestinal tight junction (TJ) barrier. Consistent with their known pro-inflammatory activities, pro-inflammatory cytokines cause a disturbance in intestinal TJ barrier, allowing increased tissue penetration of luminal antigens. Recent studies indicate that the inhibition of cytokine induced increase in intestinal TJ permeability has an important protective effect against intestinal mucosal damage and development of intestinal inflammation. In this review, the effects of various pro-inflammatory and anti-inflammatory cytokines on intestinal TJ barrier and the progress into the mechanisms that mediate the cytokine modulation of intestinal TJ barrier are reviewed.
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Affiliation(s)
- Rana Al-Sadi
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
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Chintalacharuvu SR, Yamashita M, Bagheri N, Blanchard TG, Nedrud JG, Lamm ME, Tomino Y, Emancipator SN. T cell cytokine polarity as a determinant of immunoglobulin A (IgA) glycosylation and the severity of experimental IgA nephropathy. Clin Exp Immunol 2008; 153:456-62. [PMID: 18637102 DOI: 10.1111/j.1365-2249.2008.03703.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Immunoglobulin A (IgA) glycosylation, recognized as an important pathogenic factor in IgA nephropathy (IgAN), is apparently controlled by the polarity of T helper (Th) cytokine responses. To examine the role of cytokine polarity in IgAN, inbred mice were immunized by intraperitoneal priming with inactivated Sendai virus (SeV) emulsified in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA), which promote Th1- or Th2-immune response, respectively, and then boosted identically twice orally with aqueous suspensions of inactivated virus. Next, some mice were challenged intranasally with infectious SeV. Mice primed with CFA or IFA had equal reductions in nasal viral titre relative to non-immune controls, and equally increased serum levels of SeV-specific IgA antibody. Mice primed with CFA showed higher SeV-specific IgG than those with IFA. Splenocytes from mice primed with IFA produced copious amounts of interleukin (IL)-4 and IL-5, but little interferon-gamma and IL-2; those primed with CFA had reciprocal cytokine recall responses. Total serum IgA and especially SeV-specific IgA from mice primed with IFA showed a selective defect in sialylation and galactosylation. Although the frequency and intensity of glomerular deposits and haematuria did not differ, glomerulonephritis in mice primed with IFA and challenged with infectious virus was more severe than in those given CFA, as judged by serum creatinine level. We conclude that the polarity of T cell cytokines controls the pattern of IgA glycosylation and exerts direct or indirect effects on functional glomerular responses to immune complex deposition.
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Affiliation(s)
- S R Chintalacharuvu
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
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Mathieson PW. Minimal change nephropathy and focal segmental glomerulosclerosis. Semin Immunopathol 2007; 29:415-26. [DOI: 10.1007/s00281-007-0094-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Accepted: 09/04/2007] [Indexed: 11/28/2022]
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Satchell SC, Buchatska O, Khan SB, Bhangal G, Tasman CH, Saleem MA, Baker DP, Lobb RR, Smith J, Cook HT, Mathieson PW, Pusey CD. Interferon-beta reduces proteinuria in experimental glomerulonephritis. J Am Soc Nephrol 2007; 18:2875-84. [PMID: 17942968 DOI: 10.1681/asn.2006101104] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Interferon-beta (IFN-beta) is a multifunctional cytokine with immunomodulatory properties. We examined the effect of IFN-beta in three separate rat models of glomerular injury and in cultured human glomerular endothelial cells and podocytes. In nephrotoxic nephritis in WKY rats, recombinant rat IFN-beta started either at induction or after establishment of disease significantly reduced 24-h proteinuria by up to 73% and 51%, respectively, but did not affect serum creatinine. There was a slight reduction in numbers of glomerular macrophages, but no difference in glomerular or tubulointerstitial scarring. In Thy-1 nephritis in Lewis rats, IFN-beta started at induction of disease reduced proteinuria by up to 66% with no effect on numbers of glomerular macrophages, but a reduced number of proliferating cells. In puromycin nephropathy in Wistar rats, IFN-beta started at induction of disease reduced proteinuria by up to 93%, but had no effect on glomerular histology. In cultured cells, human IFN-beta-1a had a dramatic effect on barrier properties, increasing electrical resistance across monolayers of either glomerular endothelial cells or podocytes and decreasing trans-monolayer passage of albumin. In conclusion, these results show that IFN-beta reduces proteinuria in three different rat models of glomerular injury and that its anti-proteinuric action may result from direct effects on cells that comprise the glomerular filtration barrier. These data indicate that IFN-beta may have potential as a therapeutic agent in proteinuric renal disease.
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Affiliation(s)
- Simon C Satchell
- Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, UK.
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Lai KW, Wei CL, Tan LK, Tan PH, Chiang GSC, Lee CGL, Jordan SC, Yap HK. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol 2007; 18:1476-85. [PMID: 17429054 DOI: 10.1681/asn.2006070710] [Citation(s) in RCA: 152] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
IL-13 has been implicated in the pathogenesis of minimal-change nephrotic syndrome. This study aimed to investigate the role of IL-13 on the development of proteinuria and expression of podocyte-related genes that are associated with nephrotic syndrome. IL-13 was overexpressed in Wistar rats through transfection of a mammalian expression vector cloned with the rat IL-13 gene, into the quadriceps by in vivo electroporation. Serum IL-13, albumin, cholesterol, and creatinine and urine albumin were measured serially. Kidneys were harvested after day 70 for histology and electron microscopy. Glomerular gene expression of nephrin, podocin, dystroglycan, B7-1, and IL-13 receptor subunits were examined using real-time PCR with hybridization probes and expressed as an index against beta-actin. Protein expression of these molecules was determined by immunofluorescence staining. The IL-13-transfected rats (n = 41) showed significant albuminuria, hypoalbuminemia, and hypercholesterolemia when compared with control rats (n = 17). No significant histologic changes were seen in glomeruli of IL-13-transfected rats. However, electron microscopy showed up to 80% of podocyte foot process fusion. Glomerular gene expression was significantly upregulated for B7-1, IL-4Ralpha, and IL-13Ralpha2 but downregulated for nephrin, podocin, and dystroglycan. Immunofluorescence staining intensity was reduced for nephrin, podocin, and dystroglycan but increased for B7-1 and IL-4Ralpha in IL-13-transfected rats compared with controls. In conclusion, these results suggest that IL-13 overexpression in the rat could lead to podocyte injury with downregulation of nephrin, podocin, and dystroglycan and a concurrent upregulation of B7-1 in the glomeruli, inducing a minimal change-like nephropathy that is characterized by increased proteinuria, hypoalbuminemia, hypercholesterolemia, and fusion of podocyte foot processes.
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Affiliation(s)
- Kin-Wai Lai
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Audard V, Larousserie F, Grimbert P, Abtahi M, Sotto JJ, Delmer A, Boue F, Nochy D, Brousse N, Delarue R, Remy P, Ronco P, Sahali D, Lang P, Hermine O. Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: Report of 21 cases and review of the literature. Kidney Int 2006; 69:2251-60. [PMID: 16672913 DOI: 10.1038/sj.ki.5000341] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin's lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma.
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Affiliation(s)
- V Audard
- Department of Nephrology, Henri Mondor Hospital, Paris 12 University, Creteil, Paris, France
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Le Berre L, Hervé C, Buzelin F, Usal C, Soulillou JP, Dantal J. Renal macrophage activation and Th2 polarization precedes the development of nephrotic syndrome in Buffalo/Mna rats. Kidney Int 2006; 68:2079-90. [PMID: 16221207 DOI: 10.1111/j.1523-1755.2005.00664.x] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND At 8 weeks, Buffalo/Mna rats spontaneously develop a nephrotic syndrome associated with focal segmental glomerulosclerosis (FSGS). We have previously demonstrated that this glomerulopathy recurs after renal transplantation, thus supporting the relevance of this rat model to human idiopathic nephrotic syndrome [1]. In this study, we describe renal immune abnormalities which appear in parallel to the initiation and progression of the spontaneous Buffalo/Mna nephropathy. METHODS Buffalo/Mna rat kidney samples were harvested before (4 weeks) and after the occurrence of proteinuria (at 10, 18, and 24 weeks, and at 12, 15, 18, and 24 months). Renal immune cell populations [total lymphocytes, macrophages, T, B, and natural killer (NK) cells] and the expression kinetics of various related cytokine [transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-1, IL-2, IL-4, IL-6, IL-10, IL-12, and IL-13], chemokine [regulated upon activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein-l (MCP-1)] and T-cell receptor beta (TCR beta) chain transcripts were studied serially during the course of the disease. RESULTS In the Buffalo/Mna kidneys, in parallel to the proteinuria, the focal and segmental glomerular lesions began to develop at 10 weeks (affecting 2.4 +/- 0.8% of glomeruli), increased in number, then in intensity (10.4 +/- 0.8% at 24 weeks, 14.6 +/- 2.3% at 12 months, and 28.9 +/- 7.4% at 18 months). Before the onset of the disease, at a nonproteinuric stage, the transcript expression analysis revealed a strong production of some macrophage-associated cytokines, particularly TNF-alpha (350-fold higher than control levels), which was corroborated by monocyte infiltration. A minor T-cell infiltrate (associated with an increase in Cbeta TCR transcripts), with a predominantly Th2 profile and the down-regulation of Th1 cytokines was also observed. These abnormal macrophage and T-cell patterns remained stable after the onset of the disease. No changes in chemokine and TGF-beta transcripts were observed during the initial stages of the disease. CONCLUSION Our data suggest that the Buffalo/Mna rat disease may be the result of an immunologic disorder, involving macrophages and Th2 lymphocytes. We hypothesize that this modified environment could result in the production of a factor deleterious to the glomeruli. Thus, this rat strain could provide a new model for the study of human nephrotic syndrome.
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Affiliation(s)
- Ludmilla Le Berre
- Institut National de la Santé Et de la Recherche Médicale (INSERM) Unité 643 Immunointervention dans les Allo et Xenotransplantations, Nantes, France
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Wei CL, Cheung W, Heng CK, Arty N, Chong SS, Lee BW, Puah KL, Yap HK. Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease. Nephrol Dial Transplant 2005; 20:728-34. [PMID: 15728267 DOI: 10.1093/ndt/gfh648] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Minimal-change nephrotic syndrome (MCNS) has been associated with atopy. As interleukin-13 (IL-13) has been implicated in the pathogenesis of MCNS, we postulated that IL-13 genetic polymorphisms could influence either susceptibility or clinical course of the disease. METHODS Seventy-two Singapore Chinese children with MCNS and 78 normal controls were screened for single nucleotide polymorphisms (SNPs) in the IL-13 gene by direct sequencing. Allele and genotype frequencies of these SNPs were determined and their relationship with different clinical courses was analysed. RESULTS Six SNPs were identified in the 5' promoter, exon 4 and 3' untranslated region (3'UTR). The three SNPs in the 3'UTR--4738 (G/A), 4793 (C/A) and 4926 (C/T)--were in tight linkage disequilibrium (Delta > or = 0.99). There was no difference in allele or genotype frequencies between MCNS children and normal controls. However, there was a significantly lower frequency of allele 4738G in those MCNS children who were still relapsing after 5 years of follow-up (G = 0.52), compared with those in complete remission (G = 0.72; P<0.05) and normal controls (G = 0.69; P<0.05). Haplotype analysis showed a significantly higher frequency of the GCC haplotype in controls and MCNS patients in complete remission (chi2 = 6.35; P<0.02), while the frequency of AAT haplotype was higher in those MCNS children still relapsing after 5 years of follow-up (chi2 = 5.38; P<0.02). Moreover, peripheral blood mononuclear cell IL-13 mRNA expression in patients with haplotype AAT was significantly higher than in those with haplotype GCC. CONCLUSIONS These results suggest that genetic polymorphisms in the 3'UTR of the IL-13 gene correlate with long-term outcome of MCNS, rather than disease susceptibility, in Singapore Chinese children.
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Affiliation(s)
- Chang-Li Wei
- Department of Pediatrics, National University of Singapore, 10 Lower Kent Ridge Crescent, 119074 Singapore
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Takeda E, Yamamoto H, Nashiki K, Sato T, Arai H, Taketani Y. Inorganic phosphate homeostasis and the role of dietary phosphorus. J Cell Mol Med 2005; 8:191-200. [PMID: 15256067 PMCID: PMC6740209 DOI: 10.1111/j.1582-4934.2004.tb00274.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium-dependent phosphate (Na/Pi) cotransporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by Pi, parathyroid hormone and by 1,25-dihydroxyvitamin D. Recent studies of inherited and acquired hypophosphatemia [X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO)], which exhibit similar biochemical and clinical features, have led to the identification of novel genes, PHEX and FGF23, that play a role in the regulation of Pi homeostasis. The PHEX gene, which is mutated in XLH, encodes an endopeptidase, predominantly expressed in bone and teeth, but not in kidney. FGF-23 may be a substrate of this endopeptidase and may therefore accumulate in patients with XLH. In the case of ADHR mutations in the furin cleavage site, which prevent the processing of FGF-23 into fragments, lead to the accumulation of a "stable" circulating form of the peptide which also inhibits renal Pi reabsorption. In the case of TIO, ectopic overproduction of FGF-23 overwhelms its processing and degradation by PHEX, leading to the accumulation of FGF-23 in the circulation and inhibition of renal Pi reabsorption. Mice homozygous for severely hypomorphic alleles of the Klotho gene exhibit a syndrome resembling human aging, including atherosclerosis, osteoporosis, emphysema, and infertility. The KLOTHO locus is associated with human survival, defined as postnatal life expectancy, and longevity, defined as life expectancy after 75. In considering the relationship of klotho expression to the dietary Pi level, the klotho protein seemed to be negatively controlled by dietary Pi.
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Affiliation(s)
- Eiji Takeda
- Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho 3-18-15, Tokushima, 770-8503, Japan.
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van den Berg JG, Weening JJ. Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome. Clin Sci (Lond) 2004; 107:125-36. [PMID: 15157184 DOI: 10.1042/cs20040095] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2004] [Revised: 05/11/2004] [Accepted: 05/25/2004] [Indexed: 12/19/2022]
Abstract
Idiopathic NS (nephrotic syndrome) is characterized by massive proteinuria, due to a leak in the glomerular barrier to proteins. Genetic defects that affect the function and the composition of the glomerular capillary wall, in particular of the visceral epithelial cells, have recently been recognized as the cause of familial forms of NS. MCNS (minimal change NS) and FSGS (focal and segmental glomerulosclerosis) are common non-familial forms of NS in which the causative defect has not yet been identified. Several studies have shown that non-familial NS is associated with the presence of circulating permeability factors and with complex disturbances in the immune system. Thus far, there is no direct evidence that these factors directly alter glomerular permeability to proteins, and some of these factors may be a consequence, rather than a cause, of NS. In this review, we will briefly highlight the mechanisms that underlie proteinuria in general and focus on the immunological disturbances associated with idiopathic NS, with attention to potential mechanisms whereby the immune system may directly act on the glomerular capillary filter.
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Affiliation(s)
- José G van den Berg
- Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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Reiser J, Oh J, Shirato I, Asanuma K, Hug A, Mundel TM, Honey K, Ishidoh K, Kominami E, Kreidberg JA, Tomino Y, Mundel P. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem 2004; 279:34827-32. [PMID: 15197181 DOI: 10.1074/jbc.m401973200] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and alpha(3) integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking alpha(3) integrin. Similarly, acute functional inhibition of alpha(3) integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Down-regulation of alpha(3) integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and alpha(3) integrin.
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Affiliation(s)
- Jochen Reiser
- Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
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Affiliation(s)
- P W Mathieson
- University of Bristol, Southmead Hospital, Bristol, UK.
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Steiner GE, Stix U, Handisurya A, Willheim M, Haitel A, Reithmayr F, Paikl D, Ecker RC, Hrachowitz K, Kramer G, Lee C, Marberger M. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. J Transl Med 2003; 83:1131-46. [PMID: 12920242 DOI: 10.1097/01.lab.0000081388.40145.65] [Citation(s) in RCA: 145] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The aim of the study is to characterize the type of immune response in benign prostatic hyperplasia (BPH) tissue. BPH tissue-derived T cells (n = 10) were isolated, activated (PMA + ionomycin), and analyzed for intracellular reactivity with anti-IFN-gamma and IL-2, -4, -5, -6, -10, and -13, as well as TNF-alpha and -beta by four-color flow cytometry. Lymphokine release was tested using Th1/Th2 cytokine bead arrays. The amount of IFN-gamma and IL-2, -4, -13, and TGF-beta mRNA expressed in normal prostate (n = 5) was compared with that in BPH tissue separated into segments with normal histology (n = 5), BPH histology with (n = 10) and without (n = 10) lymphocytic infiltration, and BPH nodules (n = 10). Expression of lymphokine receptors was analyzed by immunohistology, flow cytometry, and RT-PCR. We found that 28 +/- 18% of BPH T helper cells were IFN-gamma(+)/IL-4(-) Th1 cells, 10 +/- 2% were IFN-gamma(-)/IL-4(+) Th2, and 12 +/- 6% were IFN-gamma(+)/IL-4(+) Th0 cells. In relation, cytotoxic and double-negative BPH T lymphocytes showed a slight decrease in Th1 and Th0 in favor of Th2. In double-positive BPH T lymphocytes, the trend toward Th2 (35 +/- 15%) was significant (Th1: 12 +/- 7%; Th0: 5 +/- 4%). Lymphokine release upon stimulation was found in the case of IL-2, IL-5, IFN-gamma, and TNF-alpha > 4 microg; of IL-4 > 2 microg; and of IL-10 > 1 microg/ml. Expression of lymphokine mRNA in tissue was increased (2- to 10-fold) in infiltrated BPH specimens with and without BPH histology. The infiltrated BPH specimens with normal histology differed from those with BPH histology, most evident by the significant decrease in IFN-gamma and the increase in TGF-beta mRNA expression. Infiltrated BPH specimens with BPH histology expressed significantly more IFN-gamma (5-fold), IL-2 (10-fold), and IL-13 (2.8-fold) when compared with noninfiltrated BPH specimens. BPH nodules, however, showed the highest level of expression of IL-4 and IL-13, with only intermediate levels of IFN-gamma and very low levels of IL-2 mRNA. Immune response in histologically less transformed BPH specimens is primarily of type 1, whereas in chronically infiltrated nodular BPH and especially within BPH nodules, it is predominantly of type 0 or type 2.
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Affiliation(s)
- Georg E Steiner
- Department of Urology, University of Vienna Medical School, Vienna, Austria.
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Abstract
Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.
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Affiliation(s)
- Hermann Pavenstädt
- Division of Nephrology, Department of Medicine, University Hospital Freiburg, Freiburg, Germany.
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Madden KB, Whitman L, Sullivan C, Gause WC, Urban JF, Katona IM, Finkelman FD, Shea-Donohue T. Role of STAT6 and mast cells in IL-4- and IL-13-induced alterations in murine intestinal epithelial cell function. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:4417-22. [PMID: 12370375 DOI: 10.4049/jimmunol.169.8.4417] [Citation(s) in RCA: 129] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastrointestinal nematode infections generally invoke a type 2 cytokine response, characterized by the production of IL-4, IL-5, IL-9, and IL-13. Among these cytokines, IL-4 and IL-13 exhibit a functional overlap that can be explained by the sharing of a common receptor or receptor component (IL-4Ralpha). Binding of IL-4 by either the type 1 or 2 IL-4R, or of IL-13 by the type 2 IL-4R, initiates Jak-dependent tyrosine phosphorylation of the IL-4Ralpha-chain and the transcription factor, STAT6. In the present study, we investigated: 1) whether IL-13 has effects on intestinal epithelial cells similar to those observed with IL-4, and 2) whether the effects of IL-4 and IL-13 depend on STAT6 signaling and/or mast cells. BALB/c, STAT6(-/-), and mast cell-deficient W/W(v) mice or their +/+ littermates were treated with a long-lasting formulation of recombinant mouse IL-4 (IL-4C) or with IL-13 for seven days. Segments of jejunum were mounted in Ussing chambers to measure mucosal permeability; chloride secretion in response to PGE(2), histamine, 5-hydroxytryptamine, or acetylcholine; and Na(+)-linked glucose absorption. IL-4C and IL-13 increased mucosal permeability, decreased glucose absorption, and decreased chloride secretion in response to 5-hydroxytryptamine. These effects were dependent on STAT6 signaling. Responses to PGE(2) and histamine, which were dependent on mast cells and STAT6, were enhanced by IL-4C, but not by IL-13. The effects of IL-4 and IL-13 on intestinal epithelial cell function may play a critical role in host protection against gastrointestinal nematodes.
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Affiliation(s)
- Kathleen B Madden
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
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Liu S, Guo R, Tu Q, Quarles LD. Overexpression of Phex in osteoblasts fails to rescue the Hyp mouse phenotype. J Biol Chem 2002; 277:3686-97. [PMID: 11713245 DOI: 10.1074/jbc.m107707200] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Inactivating mutations of Phex, a phosphate-regulating endopeptidase, cause hypophosphatemia and impaired mineralization in X-linked hypophosphatemia (XLH) and its mouse homologue, Hyp. Because Phex is predominantly expressed in bone and cultured osteoblasts from Hyp mice display an apparent intrinsic mineralization defect, it is thought that reduced expression of Phex in mature osteoblasts is the primary cause of XLH. To test this hypothesis, we studied both targeted expression of Phex to osteoblasts in vivo under the control of the mouse osteocalcin (OG2) promoter and retroviral mediated overexpression of Phex in Hyp-derived osteoblasts (TMOb-Hyp) in vitro. Targeted overexpression of Phex to osteoblasts of OG2 Phex transgenic Hyp mice normalized Phex endopeptidase activity in bone but failed to correct the hypophosphatemia, rickets, or osteomalacia. OG2 Phex transgenic Hyp mice did exhibit a small, but significant, increase in bone mineral density and dry ashed weight, suggesting a partial mineralization effect from restoration of Phex function in mature osteoblasts. Similarly, retroviral mediated overexpression of Phex in TMOb-Hyp osteoblasts restored Phex mRNA levels, protein expression, and endopeptidase activity but failed to correct their intrinsic mineralization defect. In addition, we failed to detect the Phex substrate FGF-23 in osteoblasts. Taken together, these in vivo and in vitro data indicate that expression of Phex in osteoblasts is not sufficient to rescue the Hyp phenotype and that other sites of Phex expression and/or additional factors are likely to be important in the pathogenesis of XLH.
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Affiliation(s)
- Shiguang Liu
- Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
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Danahay H, Atherton H, Jones G, Bridges RJ, Poll CT. Interleukin-13 induces a hypersecretory ion transport phenotype in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2002; 282:L226-36. [PMID: 11792627 DOI: 10.1152/ajplung.00311.2001] [Citation(s) in RCA: 135] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Interleukin (IL)-13 has been associated with asthma, allergic rhinitis, and chronic sinusitis, all conditions where an imbalance in epithelial fluid secretion and absorption could impact upon the disease. We have investigated the effects of IL-13 on the ion transport characteristics of human bronchial epithelial cells cultured at an apical-air interface. Ussing chamber studies indicated that 48 h pretreatment with IL-13 or IL-4 significantly reduced the basal short-circuit current (I(sc)) and inhibited the amiloride-sensitive current by >98%. Furthermore, the I(sc) responses were increased by more than six- and twofold over control values when stimulated with UTP or forskolin, respectively, after cytokine treatment. The IL-13-enhanced response to UTP/ionomycin was sensitive to bumetanide and DIDS and was reduced in a low-chloride, bicarbonate-free solution. Membrane permeablization studies indicated that IL-13 induced the functional expression of an apical Ca(2+)-activated anion conductance and that changes in apical or basolateral K(+) conductances could not account for the increased I(sc) responses to UTP or ionomycin. The results indicate that IL-13 converts the human bronchial epithelium from an absorptive to a secretory phenotype that is the result of loss of amiloride-sensitive current and an increase in a DIDS-sensitive apical anion conductance.
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Affiliation(s)
- Henry Danahay
- Novartis Respiratory Research Centre, Horsham, West Sussex RH12 5AB, United Kingdom.
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Van Den Berg JG, Aten J, Annink C, Ravesloot JH, Weber E, Weening JJ. Interleukin-4 and -13 promote basolateral secretion of H(+) and cathepsin L by glomerular epithelial cells. Am J Physiol Renal Physiol 2002; 282:F26-33. [PMID: 11739109 DOI: 10.1152/ajprenal.0102.2001] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Minimal change nephrosis (MCN) is characterized by massive proteinuria and ultrastructural alterations of glomerular visceral epithelial cells (GVEC). MCN has been associated with elevated production of interleukin (IL)-13 by circulating T lymphocytes and with T helper 2 lymphocyte-dependent conditions. We recently showed that GVEC express IL-4 and IL-13 receptors and that IL-4 and IL-13 increase transcellular ion transport over GVEC monolayers. We therefore hypothesized that IL-13 may directly injure GVEC. Here we demonstrate that IL-4 and IL-13 induce bafilomycin A1-sensitive basolateral proton secretion by cultured GVEC, indicating involvement of vacuolar H(+)-ATPase. The effects of IL-4 and IL-13 were accompanied by redistribution of the small GTPases Rab5b and Rab7, as shown by confocal immunofluorescence studies. Furthermore, Western blot analysis and assays for cysteine proteinase activity revealed basolateral secretion of the lysosomal proteinase procathepsin L by cultured GVEC, stimulated by IL-4 and IL-13. We speculate that IL-4 and IL-13 influence intracellular trafficking of proteins and promote proteolysis at the basolateral surface of GVEC, which may play a pathogenic role in altered glomerular permeability.
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Affiliation(s)
- José G Van Den Berg
- Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
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Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 2001. [DOI: 10.1172/jci200114629] [Citation(s) in RCA: 222] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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