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      The important roles and molecular mechanisms of annexin A 2 autoantibody in children with nephrotic syndrome

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          Abstract

          Background

          In recent years, B-cell dysfunction has been found to play an important role in the pathogenesis of primary nephrotic syndrome (PNS). B cells play a pathogenic role by secreting antibodies against their target antigens after transforming into plasma cells. Therefore, this study aimed to screen the autoantibodies that cause PNS and explore their pathogenic mechanisms.

          Methods

          Western blotting and mass spectrometry were employed to screen and identify autoantibodies against podocytes in children with PNS. Both in vivo and in vitro experiments were used to study the pathogenic mechanism of PNS. The results were confirmed in a large multicenter clinical study in children.

          Results

          Annexin A 2 autoantibody was highly expressed in children with PNS with a pathological type of minimal change disease (MCD) or focal segmental glomerulosclerosis without genetic factors. The mouse model showed that anti-Annexin A 2 antibody could induce proteinuria in vivo. Mechanistically, the effect of Annexin A 2 antibody on the Rho signaling pathway was realized through promoting the phosphorylation of Annexin A 2 at Tyr24 on podocytes by reducing its binding to PTP1B, which led to the cytoskeletal rearrangement and damage of podocytes, eventually causing proteinuria and PNS.

          Conclusions

          Annexin A 2 autoantibody may be responsible for some cases of PNS with MCD/FSGS in children.

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          Most cited references39

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          Minimal Change Disease.

          Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
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            Idiopathic nephrotic syndrome in children

            The incidence of idiopathic nephrotic syndrome (NS) is 1·15-16·9 per 100 000 children, varying by ethnicity and region. The cause remains unknown but the pathogenesis of idiopathic NS is thought to involve immune dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. Genetic risk is more commonly described among children with steroid-resistant disease. The mainstay of therapy is prednisone for the vast majority of patients who are steroid responsive; however, the disease can run a frequently relapsing course, necessitating the need for alternative immunosuppressive agents. Infection and venous thromboembolism are the main complications of NS with also increased risk of acute kidney injury. Prognosis in terms of long-term kidney outcome overall is excellent for steroid-responsive disease, and steroid resistance is an important determinant of future risk of chronic or end-stage kidney disease.
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              Podocyte biology and response to injury.

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                Author and article information

                Journal
                Ann Transl Med
                Ann Transl Med
                ATM
                Annals of Translational Medicine
                AME Publishing Company
                2305-5839
                2305-5847
                September 2021
                September 2021
                : 9
                : 18
                : 1452
                Affiliations
                [1 ]Department of Clinical Laboratory, The Children’s Hospital of Zhejiang University School of Medicine , deptNational Clinical Research Center for Child Health , Hangzhou, China;
                [2 ]Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine , deptNational Clinical Research Center for Child Health , Hangzhou, China;
                [3 ]deptDepartment of Pediatric Nephrology , The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University , Wenzhou, China;
                [4 ]Department of Nephrology, Children’s Hospital of Fudan University , deptNational Pediatric Medical Center of China , Shanghai, China;
                [5 ]Department of Pathology, The Children’s Hospital of Zhejiang University School of Medicine , deptNational Clinical Research Center for Child Health , Hangzhou, China;
                [6 ]deptDepartment of Nephrology , Children’s Hospital of Nanjing Medical University , Nanjing, China;
                [7 ]deptDepartment of Pediatrics , First Affiliated Hospital of Zhengzhou University , Zhengzhou, China;
                [8 ]deptDepartment of Pediatric Nephrology , The First Affiliated Hospital of Guangxi Medical University , Nanning, China;
                [9 ]Department of Thoracic and Cardiovascular Surgery, The Children’s Hospital of Zhejiang University School of Medicine , deptNational Clinical Research Center for Child Health , Hangzhou, China
                Author notes

                Contributions: (I) Conception and design: J Mao, Q Shu; (II) Administrative support: J Mao, Q Shu; (III) Provision of study materials or patients: Q Ye; (IV) Collection and assembly of data: Q Ye, Y Zhang, J Zhuang, Y Bi, H Xu, Q Shen, J Liu, H Fu, J Wang, C Feng, X Tang, F Liu, W Gu, F Zhao, J Zhang, Y Qin, H Shen, A Liu, Y Xia, Z Lu; (V) Data analysis and interpretation: Q Ye, Y Zhang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                [#]

                These authors contributed equally to this work.

                Correspondence to: Jianhua Mao. Department of Nephrology, the Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China. Email: maojh88@ 123456zju.edu.cn ; Qiang Shu. Department of Thoracic and Cardiovascular Surgery, the Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China. Email: shuqiang@ 123456zju.edu.cn .
                Article
                atm-09-18-1452
                10.21037/atm-21-3988
                8506724
                34734004
                bbfefdc5-fdcc-4f82-89e4-068bc626af30
                2021 Annals of Translational Medicine. All rights reserved.

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                : 23 July 2021
                : 01 September 2021
                Categories
                Original Article

                chronic kidney disease,nephrotic syndrome,pediatric nephrology,podocyte,cytoskeleton

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