Academic Journal
Complement factor H supplementation rather than complete C3 knockout provides therapeutic benefits in IgA nephropathy.
| Τίτλος: | Complement factor H supplementation rather than complete C3 knockout provides therapeutic benefits in IgA nephropathy. |
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| Συγγραφείς: | Li X; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Ni X; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Yuan X; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Wu H; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Shi S; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Liu L; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Lv J; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Zhang H; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.; Peking University Institute of Nephrology, Beijing, 100034, China.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China., Zhu L; Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China. funnyzhuli@bjmu.edu.cn.; Peking University Institute of Nephrology, Beijing, 100034, China. funnyzhuli@bjmu.edu.cn.; Key Laboratory of Renal Disease (Peking University), National Health Commission, Beijing, 100034, China. funnyzhuli@bjmu.edu.cn.; Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China. funnyzhuli@bjmu.edu.cn.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China. funnyzhuli@bjmu.edu.cn. |
| Πηγή: | Molecular biomedicine [Mol Biomed] 2026 Apr 30; Vol. 7 (1). Date of Electronic Publication: 2026 Apr 30. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Springer Singapore Country of Publication: Singapore NLM ID: 9918283581406676 Publication Model: Electronic Cited Medium: Internet ISSN: 2662-8651 (Electronic) Linking ISSN: 26628651 NLM ISO Abbreviation: Mol Biomed Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Singapore : Springer Singapore, [2020]- |
| Ιατρικοί όροι (MeSH): | Glomerulonephritis, IGA*/pathology , Glomerulonephritis, IGA*/drug therapy , Glomerulonephritis, IGA*/immunology , Glomerulonephritis, IGA*/genetics , Complement Factor H*/pharmacology , Complement Factor H*/administration & dosage , Complement Factor H*/metabolism , Complement Factor H*/therapeutic use , Complement C3*/deficiency , Complement C3*/genetics , Complement C3*/metabolism, Immunoglobulin A/metabolism ; Immunoglobulin A/immunology ; Macrophages/metabolism ; Macrophages/immunology ; Animals ; Humans ; Mice, Knockout ; Complement Activation ; Mice ; Female ; Disease Models, Animal ; Male |
| Περίληψη: | IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by mesangial IgA deposition, which triggers complement activation, primarily through the alternative pathway. While complement dysregulation contributes to kidney injury and adverse outcomes, complement may also facilitate clearance of pathogenic immune complexes. Here, we compared complete complement component 3 (C3) deficiency with supplementation of complement factor H (Cfh), the principal regulator of alternative pathway, in murine IgAN models. C3 deficiency prevented complement activation but paradoxically increased glomerular IgA deposition and macrophage infiltration, resulting in complicated inflammatory response. In contrast, Cfh supplementation reduced glomerular IgA and C3 deposition, decreased inflammatory cytokine expression, attenuated macrophage infiltration, lessened glomerular area and ameliorated proteinuria while enhancing macrophage-mediated phagocytosis of circulating IgA immune complexes. Accordingly, IgAN patients with higher plasma CFH levels exhibited reduced mesangial IgA and C3 deposition alongside elevated circulating C3 levels, supporting CFH's protective role in regulating complement activation and promoting immune complex clearance. Our results reveal complement's dual role in IgAN: promoting inflammatory kidney injury while facilitating clearance of pathogenic IgA deposits. Targeted complement regulation via complement factor H supplementation, rather than complete complement inhibition via global complement component 3 knockout, achieves superior therapeutic effects by simultaneously controlling complement activation, enhancing immune complex clearance, suppressing inflammation, and reducing proteinuria. These findings identify complement factor H as a novel and promising therapeutic strategy for IgA nephropathy through targeted complement regulation. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the principles of the Declaration of Helsinki [54]. All procedures involving human participants were approved by the Ethics Committee of Peking University First Hospital (approval No. 2025R0547), and written informed consent was obtained from all patients. All animal experiments were performed following the guidelines of and with the approval of the Laboratory Animal Care and Use Committee at Peking University First Hospital (approval No. J2024096). Consent for publication: The authors affirm that human research participants provided informed consent for publication of the Table 1. Competing interests: All authors declare that they have no conflict of interest. |
| References: | Front Immunol. 2021 Dec 09;12:752916. (PMID: 34956184) Nat Rev Nephrol. 2025 Jan;21(1):9-23. (PMID: 39232245) Immunol Rev. 2023 Jan;313(1):25-45. (PMID: 36382387) Int Immunopharmacol. 2025 May 8;154:114544. (PMID: 40157080) Immunology. 1987 Feb;60(2):255-60. (PMID: 3817872) Nature. 2024 Jan;625(7994):377-384. (PMID: 38057668) Kidney Int. 2005 Feb;67(2):602-12. (PMID: 15673307) N Engl J Med. 1986 Aug 21;315(8):488-95. (PMID: 2942776) J Am Soc Nephrol. 2025 Apr 01;36(4):645-656. (PMID: 39455063) Semin Immunopathol. 2021 Oct;43(5):679-690. (PMID: 34379175) Cell Mol Gastroenterol Hepatol. 2022;13(1):289-307. (PMID: 34536564) J Am Soc Nephrol. 2005 Jan;16(1):52-7. (PMID: 15574507) J Immunol. 1993 Jul 1;151(1):330-8. (PMID: 8326130) J Clin Immunol. 2014 Feb;34(2):224-32. (PMID: 24327134) Clin Kidney J. 2022 Jan 24;15(5):922-928. (PMID: 35498891) JAMA. 2025 Jan 7;333(1):71-74. (PMID: 39425955) PLoS One. 2012;7(7):e40495. (PMID: 22792353) Clin Exp Immunol. 2006 Oct;146(1):133-45. (PMID: 16968408) Kidney Int. 2007 Jun;71(11):1142-7. (PMID: 17410102) Nat Genet. 2011 Mar 13;43(4):321-7. (PMID: 21399633) Semin Thromb Hemost. 2001 Jun;27(3):191-9. (PMID: 11446652) Kidney Dis (Basel). 2025 May 9;11(1):450-468. (PMID: 40606676) J Immunol. 2013 Jul 15;191(2):912-21. (PMID: 23772024) J Am Soc Nephrol. 2015 May;26(5):1195-204. (PMID: 25205734) J Am Soc Nephrol. 2018 Feb;29(2):661-669. (PMID: 29114042) Pharmacol Rev. 2021 Apr;73(2):792-827. (PMID: 33687995) Semin Cell Dev Biol. 2019 Jan;85:122-131. (PMID: 29305301) Front Immunol. 2023 Jul 03;14:1192941. (PMID: 37529043) Clin J Am Soc Nephrol. 2024 Apr 1;19(4):452-462. (PMID: 38214599) Kidney Int. 1987 Dec;32(6):838-44. (PMID: 3430967) Kidney Int. 2015 May;87(5):930-9. (PMID: 25565310) Nat Rev Dis Primers. 2023 Nov 30;9(1):67. (PMID: 38036542) J Am Soc Nephrol. 2025 Jan 1;36(1):60-72. (PMID: 39172518) Front Immunol. 2023 Sep 11;14:1239146. (PMID: 37753090) N Engl J Med. 2025 Feb 06;392(6):531-543. (PMID: 39453772) J Clin Invest. 1984 Oct;74(4):1329-40. (PMID: 6480828) Clin J Am Soc Nephrol. 2023 Dec 1;18(12):1583-1591. (PMID: 37651123) Kidney Int. 1998 Feb;53(2):320-30. (PMID: 9461092) N Engl J Med. 2013 Jun 20;368(25):2402-14. (PMID: 23782179) Mol Ther. 2025 Aug 6;33(8):3746-3756. (PMID: 40285355) Clin J Am Soc Nephrol. 2021 Dec;16(12):1840-1850. (PMID: 34615657) J Am Soc Nephrol. 2018 Jun;29(6):1649-1661. (PMID: 29588430) Histopathology. 2021 May;78(6):882-895. (PMID: 33336446) Kidney Int. 2015 Dec;88(6):1314-1322. (PMID: 26221753) Clin J Am Soc Nephrol. 2023 Jun 1;18(6):727-738. (PMID: 37055195) Adv Ther. 2023 Mar;40(3):814-827. (PMID: 36609679) Mucosal Immunol. 2022 May;15(5):927-939. (PMID: 35672453) J Clin Invest. 1983 Feb;71(2):236-47. (PMID: 6822663) Nephrol Dial Transplant. 2020 Dec 4;35(12):2103-2137. (PMID: 31377783) Drugs. 2023 Nov;83(16):1475-1499. (PMID: 37747686) PLoS One. 2013 Aug 30;8(8):e73425. (PMID: 24023680) J Am Soc Nephrol. 2003 Dec;14(12):3127-37. (PMID: 14638911) Kidney Int Rep. 2020 Aug 13;5(11):2032-2041. (PMID: 33163724) J Exp Med. 2017 Jul 3;214(7):2103-2119. (PMID: 28606989) |
| Grant Information: | 82470734 National Science Foundation of China; 82270740 National Science Foundation of China; 82170710 National Science Foundation of China; 20230484486 Beijing Science and Technology Planning Project; 2024YFC2511000 National High Level Hospital Clinical Research Funding |
| Contributed Indexing: | Keywords: Complement activation; Complement component 3; Complement factor H; IgA nephropathy; Immune complex clearance |
| Substance Nomenclature: | 80295-65-4 (Complement Factor H) 0 (Complement C3) 0 (Immunoglobulin A) |
| Entry Date(s): | Date Created: 20260430 Date Completed: 20260716 Latest Revision: 20260813 |
| Update Code: | 20260813 |
| PubMed Central ID: | PMC13133335 |
| DOI: | 10.1186/s43556-026-00463-y |
| PMID: | 42060028 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2662-8651 |
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| DOI: | 10.1186/s43556-026-00463-y |