1
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Alkaff FF, Lammerts RGM, Daha MR, Berger SP, van den Born J. Apical tubular complement activation and the loss of kidney function in proteinuric kidney diseases. Clin Kidney J 2024; 17:sfae215. [PMID: 39135935 PMCID: PMC11318052 DOI: 10.1093/ckj/sfae215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/07/2024] [Indexed: 08/15/2024] Open
Abstract
Many kidney diseases are associated with proteinuria. Since proteinuria is independently associated with kidney function loss, anti-proteinuric medication, often in combination with dietary salt restriction, comprises a major cornerstone in the prevention of progressive kidney failure. Nevertheless, complete remission of proteinuria is very difficult to achieve, and most patients with persistent proteinuria slowly progress toward kidney failure. It is well-recognized that proteinuria leads to kidney inflammation and fibrosis via various mechanisms. Among others, complement activation at the apical side of the proximal tubular epithelial cells is suggested to play a crucial role as a cause of progressive loss of kidney function. However, hitherto limited attention is given to the pathophysiological role of tubular complement activation relative to glomerular complement activation. This review aims to summarize the evidence for tubular epithelial complement activation in proteinuric kidney diseases in relation to loss of kidney function.
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Affiliation(s)
- Firas F Alkaff
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Division of Pharmacology and Therapy, Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | - Rosa G M Lammerts
- Transplantation Immunology, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mohamed R Daha
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefan P Berger
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jacob van den Born
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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2
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Yuan Y, Cui Y, Zhao D, Yuan Y, Zhao Y, Li D, Jiang X, Zhao G. Complement networks in gene-edited pig xenotransplantation: enhancing transplant success and addressing organ shortage. J Transl Med 2024; 22:324. [PMID: 38566098 PMCID: PMC10986007 DOI: 10.1186/s12967-024-05136-4] [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] [Academic Contribution Register] [Received: 12/26/2023] [Accepted: 03/27/2024] [Indexed: 04/04/2024] Open
Abstract
The shortage of organs for transplantation emphasizes the urgent need for alternative solutions. Xenotransplantation has emerged as a promising option due to the greater availability of donor organs. However, significant hurdles such as hyperacute rejection and organ ischemia-reperfusion injury pose major challenges, largely orchestrated by the complement system, and activated immune responses. The complement system, a pivotal component of innate immunity, acts as a natural barrier for xenotransplantation. To address the challenges of immune rejection, gene-edited pigs have become a focal point, aiming to shield donor organs from human immune responses and enhance the overall success of xenotransplantation. This comprehensive review aims to illuminate strategies for regulating complement networks to optimize the efficacy of gene-edited pig xenotransplantation. We begin by exploring the impact of the complement system on the effectiveness of xenotransplantation. Subsequently, we delve into the evaluation of key complement regulators specific to gene-edited pigs. To further understand the status of xenotransplantation, we discuss preclinical studies that utilize gene-edited pigs as a viable source of organs. These investigations provide valuable insights into the feasibility and potential success of xenotransplantation, offering a bridge between scientific advancements and clinical application.
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Affiliation(s)
- Yinglin Yuan
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuanyuan Cui
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Dayue Zhao
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuan Yuan
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanshuang Zhao
- Department of Pharmacy, The People's Hospital of Leshan, Leshan, China
| | - Danni Li
- Department of Pharmacy, Longquanyi District of Chengdu Maternity & Child Health Care Hospital, Chengdu, China
| | - Xiaomei Jiang
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Gaoping Zhao
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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Kurultak I, Gungor O, Ozturk S, Dirim AB, Eren N, Yenigün E, Dal EA, Dincer MT, Bora F, Akgur S, Sumnu A, Dursun B, Sipahi S, Cetinkaya H, Sahin I, Sahin G, Yilmaz M, Vatansever B, Aydın E, Ulu MS, Gundogdu A, Ustundag S, Sayarlioglu H, Kumru G, Elcioglu OC, Aydın Z, Selcuk NY, Onal Guclu C, Oruc M, Kucuk M, Aktas N, Derici U, Suleymanlar G. Clinical and histopathological characteristics of primary focal segmental glomerulosclerosis in Turkish adults. Sci Rep 2024; 14:6748. [PMID: 38514826 PMCID: PMC10957996 DOI: 10.1038/s41598-024-57305-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/04/2023] [Accepted: 03/16/2024] [Indexed: 03/23/2024] Open
Abstract
The data regarding primary FSGS (pFSGS) from different parts of the world differ. While the prevalence of pFSGS has been increasing in Western countries like the USA, it follows an inconsistent trend in Europe and Asia and a decreasing trend in Far Eastern countries such as China in the last two decades. There are undetermined factors to explain those national and geographic discrepancies. Herein, we aimed to reveal the current prevalence with clinical and histopathological characteristics of pFSGS in Turkish adults. This study includes the biopsy-proven pFSGS patients data recorded between 2009 and 2019, obtained from the national multicenter primary glomerulonephritis registry system of the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) database. 850 of the 3875 primer glomerulonephritis patients(21.9%) have pFSGS. The mean age is 40.5 ± 14.2 and 435 (51.2%) of patients are male. Nephrotic syndrome is the most common biopsy indication (59.2%). 32.6% of patients have hematuria, 15.2% have leukocyturia and 7.8% have both. Serum creatinine, albumin, and proteinuria are 1.0 mg/dL (IQR = 0.7-1.4) mg/dl, 3.4 ± 0.9 g/dl, 3400 mg/day(IQR, 1774-5740), respectively. Females have lower mean arterial pressure (- 2.2 mmHg), higher eGFR (+ 10.0 mL/min/1.73 m2), and BMI (+ 1.6 kg/m2) than males. Thickened basal membrane(76.6%) and mesangial proliferation (53.5%) on light microscopy are the major findings after segmental sclerosis. IgM (32.7%) and C3 (32.9%) depositions are the most common findings on immunofluorescence microscopy. IgM positivity is related to lower eGFR, serum albumin, and higher proteinuria. The prevalence of pFSGS is stable although slightly increasing in Turkish adults. The characteristics of the patients are similar to those seen in Western countries.
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Affiliation(s)
- Ilhan Kurultak
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Trakya University, 22030, Edirne, Turkey.
| | - Ozkan Gungor
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Sutcu Imam University, Kahramanmaras, Turkey
| | - Savas Ozturk
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Istanbul University, Istanbul, Turkey
| | - Ahmet Burak Dirim
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Istanbul University, Istanbul, Turkey
| | - Necmi Eren
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Kocaeli University, Kocaeli, Turkey
| | - Ezgi Yenigün
- Department of Internal Medicine, Division of Nephrology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Elbis Ahbab Dal
- Department of Internal Medicine, Division of Nephrology, Health Science University, Istanbul Hamidiye Sisli Etfal Training and Research Hospital, Istanbul, Turkey
| | - Mevlut Tamer Dincer
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Feyza Bora
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Akdeniz University, Antalya, Turkey
| | - Suat Akgur
- Department of Internal Medicine, Division of Nephrology, Kutahya Health Science University, Evliya Celebi Yuksek Ihtisas Training and Research Hospital, Kutahya, Turkey
| | - Abdullah Sumnu
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Medipol University, Istanbul, Turkey
| | - Belda Dursun
- Faculty of Medicine, Department of InternalMedicine, Division of Nephrology, Pamukkale University, Denizli, Turkey
| | - Savas Sipahi
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Sakarya University, Sakarya, Turkey
| | - Hakki Cetinkaya
- Department of Internal Medicine, Division of Nephrology, Sultan Abdulhamid Training and Research Hospital, Istanbul, Turkey
| | - Idris Sahin
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Inonu University, Malatya, Turkey
| | - Garip Sahin
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Eskisehir Osmangazi University, Eskişehir, Turkey
| | - Murvet Yilmaz
- Department of Internal Medicine, Division of Nephrology, Health Science University, Bakırköy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - Bulent Vatansever
- Department of Internal Medicine, Division of Nephrology, Izmir Bozyaka Training and Research Hospital, Izmir, Turkey
| | - Emre Aydın
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Dicle University, Diyarbakir, Turkey
| | - Memnune Sena Ulu
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Afyon Kocatepe University, Afyon, Turkey
| | - Ali Gundogdu
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Erciyes University, Kayseri, Turkey
| | - Sedat Ustundag
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Trakya University, 22030, Edirne, Turkey
| | - Hayriye Sayarlioglu
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Samsun 19 Mayis University, Samsun, Turkey
| | - Gizem Kumru
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Ankara University, Ankara, Turkey
| | - Omer C Elcioglu
- Department of Internal Medicine, Division of Nephrology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey
| | - Zeki Aydın
- Department of Internal Medicine, Division of Nephrology, Darıca Farabi Training and Research Hospital, Kocaeli, Turkey
| | - Nedim Yılmaz Selcuk
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Selcuk University, Konya, Turkey
| | - Ceren Onal Guclu
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Hacettepe University, Ankara, Turkey
| | - Meric Oruc
- Department of Internal Medicine, Division of Nephrology, Kartal Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Mehmet Kucuk
- Department of Internal Medicine, Division of Nephrology, Okmeydanı Training and Research Hospital, Istanbul, Turkey
| | - Nimet Aktas
- Department of Internal Medicine, Division of Nephrology, Health Science University, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Ulver Derici
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Gazi University, Ankara, Turkey
| | - Gultekin Suleymanlar
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Akdeniz University, Antalya, Turkey
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Miwa T, Sato S, Golla M, Song WC. Expansion of Anticomplement Therapy Indications from Rare Genetic Disorders to Common Kidney Diseases. Annu Rev Med 2024; 75:189-204. [PMID: 37669567 DOI: 10.1146/annurev-med-042921-102405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 09/07/2023]
Abstract
Complement constitutes a major part of the innate immune system. The study of complement in human health has historically focused on infection risks associated with complement protein deficiencies; however, recent interest in the field has focused on overactivation of complement as a cause of immune injury and the development of anticomplement therapies to treat human diseases. The kidneys are particularly sensitive to complement injury, and anticomplement therapies for several kidney diseases have been investigated. Overactivation of complement can result from loss-of-function mutations in complement regulators; gain-of-function mutations in key complement proteins such as C3 and factor B; or autoantibody production, infection, or tissue stresses, such as ischemia and reperfusion, that perturb the balance of complement activation and regulation. Here, we provide a high-level review of the status of anticomplement therapies, with an emphasis on the transition from rare diseases to more common kidney diseases.
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Affiliation(s)
- Takashi Miwa
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; , , ,
| | - Sayaka Sato
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; , , ,
| | - Madhu Golla
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; , , ,
| | - Wen-Chao Song
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; , , ,
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5
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Abstract
The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.
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Affiliation(s)
- Vojtech Petr
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joshua M Thurman
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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6
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Whelan R, Feemster A, Laskowski J, Renner B, Kulik L, Poppelaars F, Lee C, Holers VM, Thurman JM. Female but Not Male Mice Deficient in Soluble IgM Are Susceptible to Chemically Induced Glomerular Injury. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1240-1248. [PMID: 37682538 PMCID: PMC10592129 DOI: 10.4049/jimmunol.2200292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 04/19/2022] [Accepted: 08/11/2023] [Indexed: 09/09/2023]
Abstract
B cell-targeted therapies are effective for treating multiple different kidney diseases in humans and also protect mice from Adriamycin nephropathy. Because glomerular IgM is frequently seen in both humans and mice with "nonimmune" forms of glomerular disease, we hypothesized that natural IgM binds to epitopes displayed in the injured glomerulus, exacerbating injury. To test this hypothesis, we induced Adriamycin nephropathy in BALB/C mice that cannot secrete soluble IgM (sIgM-/- mice) and compared them with BALB/C controls. Contrary to our prediction, we found that female sIgM-/- mice developed higher mortality and more severe kidney injury after injection of Adriamycin. The absence of soluble IgM did not reduce glomerular complement activation, and IgG was seen deposited within the injured glomeruli. Furthermore, we discovered that female sIgM-/- mice have higher levels of anti-cardiolipin IgG, and that IgG from these mice binds to epitopes in the injured kidney. These findings indicate that natural IgM may prevent generation of autoreactive IgG. Circulating levels of anti-cardiolipin IgG decreased after induction of kidney injury in female mice, consistent with deposition of the Abs in injured tissues. Better understanding of the mechanisms by which the immune system modulates and amplifies kidney injury may enable the development of targeted therapies to slow kidney disease progression.
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Affiliation(s)
- Russell Whelan
- Department of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew Feemster
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Jennifer Laskowski
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Brandon Renner
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Liudmila Kulik
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Felix Poppelaars
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Cameron Lee
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - V. Michael Holers
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Joshua M. Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
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7
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Amer F, Syed M, Afzal A, Hussain M, Hassan U, Bashir S, Hameed M, Ishtiaq S. IgM and C3 Deposition in Primary Focal Segmental Glomerulosclerosis (FSGS): A Clinical and Histopathological Spectrum. Cureus 2023; 15:e37346. [PMID: 37182061 PMCID: PMC10169510 DOI: 10.7759/cureus.37346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common renal disorder, characterized by progressive segmental sclerosis of renal glomeruli and clinical symptoms corresponding to proteinuria. Classically, it is not considered to be an antibody-mediated disease, however, IgM and C3 deposition may be seen in a subset of cases of FSGS. The impact of this immune deposition on histopathological features in renal core biopsies, on the urinary biochemical parameters, and the clinical outcomes, has not been previously investigated in our population. The aim of this study is to analyze the aforementioned parameters in patients with primary FSGS having antibody deposition as compared to those who do not have any antibody deposition. Some 155 patients diagnosed with FSGS were retrospectively enrolled in our study. The renal biopsies were reviewed for histopathological features and immunofluorescence (IF) findings of IgM and C3 glomerular deposition. These histological features were then compared with the biochemical parameters as well as the clinical outcomes of patients. The patients were assigned to Groups 1 and 2 based on the IF findings. The IgM and/or C3 glomerular deposition had a low incidence in patients with primary FSGS in our study (28.3%). Patients having IgM and C3 co-deposition had a significantly longer time duration since the onset of their clinical symptoms; active disease duration (42 months vs 22 months, p=0.049). The mean pre-treatment serum creatinine of patients with IgM and C3 co-deposition was 6.00 mg/dL as compared to 3.29 mg/dL in patients with no immune deposition (p=0.037). The immune deposition was associated with higher rates of segmental and global glomerulosclerosis, but this finding along with other evaluated histological parameters did not show statistical significance. The number of patients having IgM and/or C3 deposition and with active steroid use/renal dialysis was similar to patients having no IgM and/or C3 deposition. The IgM and/or C3 deposition in FSGS has a low incidence within and is not associated with any significant differences in histological parameters on renal core biopsies of patients from the Pakistani population. IgM and/or C3 deposition is also associated with a significantly longer duration of active disease and these patients may present with higher pre-treatment serum creatinine. Other biochemical parameters and clinical outcomes appear comparable between the groups based on the available clinical data.
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Affiliation(s)
- Faizan Amer
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Madiha Syed
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | | | - Mudassar Hussain
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Usman Hassan
- Pathology, Shaukat Khanum Memoiral Cancer Hospital and Research Centre, Lahore, PAK
| | - Shaarif Bashir
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Maryam Hameed
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
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8
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Bin S, Budge K, Gentile M, Podestà MA, Khan Y, Azzi JR, Sanchez Russo L, La Manna G, Cravedi P. Decay-Accelerating Factor Expression Modulates the Severity of Experimental Focal Segmental Glomerulosclerosis. KIDNEY360 2023; 4:381-386. [PMID: 36996302 PMCID: PMC10103208 DOI: 10.34067/kid.0005312022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 08/11/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022]
Abstract
Genetically induced decay-accelerating factor (DAF) overexpression prevents adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) in mice. Pharmacologic inhibition of DAF cleavage reduces complement activation in the glomeruli and albuminuria in murine ADR-induced FSGS. Inhibition of complement activation represents a valuable therapeutic strategy for FSGS and, potentially, other glomerular diseases.
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Affiliation(s)
- Sofia Bin
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Kelly Budge
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Micaela Gentile
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- Unità Operativa Nefrologia, Azienda-Ospedaliero Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Manuel Alfredo Podestà
- Renal Division, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Yaseen Khan
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jamil R. Azzi
- Transplantation Research Center, Division of Nephrology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Luis Sanchez Russo
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Paolo Cravedi
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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9
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Thurman JM, Harrison RA. The susceptibility of the kidney to alternative pathway activation-A hypothesis. Immunol Rev 2023; 313:327-338. [PMID: 36369971 DOI: 10.1111/imr.13168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/15/2022]
Abstract
The glomerulus is often the prime target of dysregulated alternative pathway (AP) activation. In particular, AP activation is the key driver of two severe kidney diseases: atypical hemolytic uremic syndrome and C3 glomerulopathy. Both conditions are associated with a variety of predisposing molecular defects in AP regulation, such as genetic variants in complement regulators, autoantibodies targeting AP proteins, or autoantibodies that stabilize the AP convertases (C3- and C5-activating enzymes). It is noteworthy that these are systemic AP defects, yet in both diseases pathologic complement activation primarily affects the kidneys. In particular, AP activation is often limited to the glomerular capillaries. This tropism of AP-mediated inflammation for the glomerulus points to a unique interaction between AP proteins in plasma and this particular anatomic structure. In this review, we discuss the pre-clinical and clinical data linking the molecular causes of aberrant control of the AP with activation in the glomerulus, and the possible causes of this tropism. Based on these data, we propose a model for why the kidney is so uniquely and frequently targeted in patients with AP defects. Finally, we discuss possible strategies for preventing pathologic AP activation in the kidney.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
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10
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Peng Y, Li B, Li X, Ju T, Zhang Z, Wang P, Sun T, Shu J, Wang M, Sun X, Chen H, Gao C, Xia Z. Glomerular capillary C3 deposition as a risk factor for unfavorable renal outcome in pediatric primary focal segmental glomerular sclerosis. Front Pediatr 2023; 11:1137375. [PMID: 37025292 PMCID: PMC10070806 DOI: 10.3389/fped.2023.1137375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/04/2023] [Accepted: 03/06/2023] [Indexed: 04/08/2023] Open
Abstract
Introduction Some patients with primary focal segmental sclerosis (FSGS) demonstrate complement 3 (C3) deposition in glomerular capillary loops (Cap-C3) and/or mesangial area (Mes-C3). The clinicopathological and prognostic significance of C3 deposition remains incompletely investigated, especially in the pediatric cohort. Methods We retrospectively analyzed 264 children of biopsy-proven primary FSGS between January 2003 and December 2020. The correlation between Cap-C3 and renal outcome was evaluated by the Kaplan-Meier method and Cox multivariate regression analysis. Renal end-point event was defined as the development of end-stage renal disease, death for renal disease, or an estimated glomerular filtration rate reduction by at least 50% from baseline. Results Among the 264 patients, 30 (11.4%) had Cap-C3. Kaplan-Meier analysis showed that patients with Cap-C3 had significantly lower renal survival rates than patients without Cap-C3 (60.17% vs. 84.71% at 5 years, 39.49% vs. 65.55% at 10 years, P < 0.01). Cox multivariate regression analysis showed that Cap-C3 was an independent risk factor for poor renal outcome (HR 3.53, 95% CI 1.22-10.19, P = 0.02). Conclusion Glomerular capillary C3 deposition was an independent risk factor for unfavorable renal outcome in children with primary FSGS.
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Affiliation(s)
- Yingchao Peng
- Department of Pediatrics, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Banghai Li
- Department of Medical Insurance Section, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Xiaojie Li
- Department of Pediatrics, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Tao Ju
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Zhiqiang Zhang
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Peipei Wang
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Tao Sun
- Department of Medical Information, Jinling Hospital, Nanjing, China
| | - Jiaping Shu
- Department of Medical Information, Jinling Hospital, Nanjing, China
| | - Meiqiu Wang
- Department of Pediatrics, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Xiaoyi Sun
- Department of Pediatrics, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
| | - Huangyu Chen
- Department of Pediatrics, Jinling Hospital, Nanjing, China
| | - Chunlin Gao
- Department of Pediatrics, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China
- Correspondence: Zhengkun Xia Chunlin Gao
| | - Zhengkun Xia
- Department of Pediatrics, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China
- Correspondence: Zhengkun Xia Chunlin Gao
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11
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Renner B, Laskowski J, Poppelaars F, Ferreira VP, Blaine J, Antonioli AH, Hannan JP, Kovacs JM, van Kooten C, You Z, Pickering MC, Holers VM, Thurman JM. Factor H related proteins modulate complement activation on kidney cells. Kidney Int 2022; 102:1331-1344. [PMID: 36063874 PMCID: PMC9691546 DOI: 10.1016/j.kint.2022.07.035] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/12/2021] [Revised: 07/04/2022] [Accepted: 07/27/2022] [Indexed: 01/13/2023]
Abstract
Complement activation at a particular location is determined by the balance of activating and inhibitory proteins. Factor H is a key regulator of the alternative pathway of complement, and genetic or acquired impairments in Factor H are associated with glomerular injury. The human Factor H-related proteins (FHRs) comprise a family of five proteins that are structurally related to Factor H. Variations in the genes or expression levels of the FHRs are also associated with glomerular disease, although the mechanisms of glomerular protection/injury are incompletely understood. To explore the role of the FHRs on complement regulation/dysregulation in the kidney, we expressed and purified recombinant murine FHRs (FHRs A, B, C and E). These four distinct FHRs contain binding regions with high amino acid sequence homology to binding regions within Factor H, but we observed different interactions of the FHRs with Factor H binding ligands, including heparin and C3d. There was differential binding of the FHRs to the resident kidney cell types (mesangial, glomerular endothelial, podocytes, and tubular epithelial). All four FHRs caused complement dysregulation on kidney cell surfaces in vitro, although the magnitude of the effect differed among the FHRs and also varied among the different kidney cells. However, only FHR E caused glomerular complement dysregulation when injected in vivo but did not exacerbate injury when injected into mice with ischemic acute kidney injury, an alternative pathway-mediated model. Thus, our experiments demonstrate that the FHRs have unique, and likely context-dependent, effects on the different cell types within the kidney.
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Affiliation(s)
- Brandon Renner
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jennifer Laskowski
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Felix Poppelaars
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Viviana P Ferreira
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Judith Blaine
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
| | | | - Jonathan P Hannan
- Molecular Biophysics Program and Department of Biochemistry, University of Colorado, Boulder, Colorado, USA
| | - James M Kovacs
- Department of Chemistry and Biochemistry, University of Colorado Springs, Colorado Springs, Colorado, USA
| | - Cees van Kooten
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Zhiying You
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Matthew C Pickering
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, UK
| | - V Michael Holers
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
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12
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Abstract
Annexin A2 is a Ca2+- and phospholipid-binding protein which is widely expressed in various types of cells and tissues. As a multifunctional molecule, annexin A2 is found to be involved in diverse cell functions and processes, such as cell exocytosis, endocytosis, migration and proliferation. As a receptor of plasminogen and tissue plasminogen activator, annexin A2 promotes plasmin generation and regulates the homeostasis of blood coagulation, fibrinolysis and matrix degradation. As an antigen expressed on cell membranes, annexin A2 initiates local inflammation and damage through binding to auto-antibodies. Annexin A2 also mediates multiple signaling pathways induced by various growth factors and oxidative stress. Aberrant expression of annexin A2 has been found in numerous kidney diseases. Annexin A2 has been shown to act as a co-receptor of integrin CD11b mediating NF-kB-dependent kidney inflammation, which is further amplified through annexin A2/NF-kB-triggered macrophage M2 to M1 phenotypic change. It also modulates podocyte cytoskeleton rearrangement through Cdc42 and Rac1/2/3 Rho pathway causing proteinuria. Thus, annexin A2 is implicated in the pathogenesis and progression of various kidney diseases. In this review, we focus on the current understanding of the role of annexin A2 in kidney diseases.
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Affiliation(s)
- Ling Lin
- *Correspondence: Ling Lin, ; Kebin Hu,
| | - Kebin Hu
- *Correspondence: Ling Lin, ; Kebin Hu,
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13
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Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis. Kidney Int Rep 2022; 7:1027-1036. [PMID: 35571000 PMCID: PMC9091805 DOI: 10.1016/j.ekir.2022.02.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/09/2021] [Revised: 01/27/2022] [Accepted: 02/04/2022] [Indexed: 12/11/2022] Open
Abstract
Introduction Methods Results Conclusion
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14
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Trachtman H, Laskowski J, Lee C, Renner B, Feemster A, Parikh S, Panzer SE, Zhong W, Cravedi P, Cantarelli C, Kulik L, You Z, Satchell S, Rovin B, Liu F, Kalled SL, Holers VM, Jalal D, Thurman JM. Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome. Am J Physiol Renal Physiol 2021; 321:F505-F516. [PMID: 34459222 DOI: 10.1152/ajprenal.00041.2021] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD.NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.
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Affiliation(s)
- Howard Trachtman
- Department of Pediatrics, Langone Medical Center, New York University School of Medicine, New York, New York
| | - Jennifer Laskowski
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
| | - Cameron Lee
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
| | - Brandon Renner
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
| | - Andrew Feemster
- Department of Pediatrics, Langone Medical Center, New York University School of Medicine, New York, New York
| | - Samir Parikh
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Sarah E Panzer
- Department of Medicine, University of Wisconsin-Madison Hospital and Clinics, Madison, Wisconsin
| | - Weixiong Zhong
- Department of Medicine, University of Wisconsin-Madison Hospital and Clinics, Madison, Wisconsin
| | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Chiara Cantarelli
- Dipartimento di Medicina e Chirurgia, Università di Parma, UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Liudmila Kulik
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
| | - Zhiying You
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
| | - Simon Satchell
- Bristol Renal, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom
| | - Brad Rovin
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Fei Liu
- Q32 Bio, Incorporated, Cambridge, Massachusetts
| | | | - V Michael Holers
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
| | - Diana Jalal
- Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Joshua M Thurman
- Department of Medicine, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado
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15
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Angeletti A, Cantarelli C, Petrosyan A, Andrighetto S, Budge K, D'Agati VD, Hartzell S, Malvi D, Donadei C, Thurman JM, Galešić-Ljubanović D, He JC, Xiao W, Campbell KN, Wong J, Fischman C, Manrique J, Zaza G, Fiaccadori E, La Manna G, Fribourg M, Leventhal J, Da Sacco S, Perin L, Heeger PS, Cravedi P. Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis. J Exp Med 2021; 217:151976. [PMID: 32717081 PMCID: PMC7478737 DOI: 10.1084/jem.20191699] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2019] [Revised: 02/28/2020] [Accepted: 04/27/2020] [Indexed: 12/24/2022] Open
Abstract
Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets.
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Affiliation(s)
- Andrea Angeletti
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.,Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
| | - Chiara Cantarelli
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.,Dipartimento di Medicina e Chirurgia Università di Parma, UO Nefrologia, Azienda Ospedaliera-Universitaria Parma, Parma, Italy
| | - Astgik Petrosyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Children's Hospital Los Angeles, Los Angeles, CA.,Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, CA
| | - Sofia Andrighetto
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.,Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Kelly Budge
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Vivette D D'Agati
- Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Susan Hartzell
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Deborah Malvi
- "F. Addarii" Institute of Oncology and Transplantation Pathology, Bologna University, Bologna, Italy
| | - Chiara Donadei
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO
| | | | - John Cijiang He
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Wenzhen Xiao
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Kirk N Campbell
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jenny Wong
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Clara Fischman
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Joaquin Manrique
- Nephrology Service, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Gianluigi Zaza
- Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Enrico Fiaccadori
- Dipartimento di Medicina e Chirurgia Università di Parma, UO Nefrologia, Azienda Ospedaliera-Universitaria Parma, Parma, Italy
| | - Gaetano La Manna
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Miguel Fribourg
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jeremy Leventhal
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Stefano Da Sacco
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Children's Hospital Los Angeles, Los Angeles, CA.,Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, CA
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Children's Hospital Los Angeles, Los Angeles, CA.,Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, CA
| | - Peter S Heeger
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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16
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Huang J, Cui Z, Gu QH, Zhang YM, Qu Z, Wang X, Wang F, Cheng XY, Meng LQ, Liu G, Zhao MH. Complement activation profile of patients with primary focal segmental glomerulosclerosis. PLoS One 2020; 15:e0234934. [PMID: 32569286 PMCID: PMC7307932 DOI: 10.1371/journal.pone.0234934] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/11/2020] [Accepted: 06/04/2020] [Indexed: 11/25/2022] Open
Abstract
Background Studies on adriamycin mice model suggest complement system is activated and together with IgM contributes to the glomerular injury of primary focal segmental glomerulosclerosis (FSGS). We recently reported primary FSGS patients with IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes. Here we examined the plasma and urinary complement profile of patients with primary FSGS, aiming to investigate the complement participation in FSGS pathogenesis. Methods Seventy patients with biopsy-proven primary FSGS were enrolled. The plasma and urinary levels of C3a, C5a, soluble C5b-9, C4d, C1q, MBL, and Bb were determined by commercial ELISA kits. Results The levels of C3a, C5a and C5b-9 in plasma and urine of FSGS patients were significantly higher than those in normal controls. The plasma and urinary levels of C5b-9 were positively correlated with urinary protein, renal dysfunction and interstitial fibrosis. The plasma C5a levels were positively correlated with the proportion of segmental sclerotic glomeruli. The urinary levels of Bb were elevated, positively correlated with C3a and C5b-9 levels, renal dysfunction, and interstitial fibrosis. The plasma C1q level was significantly decreased, and negatively correlated with urinary protein excretion. Urinary Bb level was a risk factor for no remission (HR = 3.348, 95% CI 1.264–8.870, P = 0.015) and ESRD (HR = 2.323, 95% CI 1.222–4.418, P = 0.010). Conclusion In conclusion, our results identified the systemic activation of complement in human primary FSGS, possibly via the classical and alternative pathway. The activation of complement system was partly associated with the clinical manifestations, kidney pathological damage, and renal outcomes.
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Affiliation(s)
- Jing Huang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Zhao Cui
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
- * E-mail:
| | - Qiu-hua Gu
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Yi-miao Zhang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Zhen Qu
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Xin Wang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Fang Wang
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Xu-yang Cheng
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Li-qiang Meng
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Gang Liu
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Ming-hui Zhao
- Renal Division, Peking University First Hospital, Beijing, PR China
- Institute of Nephrology, Peking University, Beijing, PR China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, PR China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
- Peking-Tsinghua Center for Life Sciences, Beijing, PR China
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17
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Thurman JM. Complement and the Kidney: An Overview. Adv Chronic Kidney Dis 2020; 27:86-94. [PMID: 32553250 DOI: 10.1053/j.ackd.2019.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2019] [Revised: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022]
Abstract
The complement cascade was first recognized as a downstream effector system of antibody-mediated cytotoxicity. Consistent with this view, it was discovered in the 1960s that complement is activated in the glomeruli of patients with immune complex glomerulonephritis. More recently, research has shown that complement system has many additional functions relating to regulation of the immune response, homeostasis, and metabolism. It has also become clear that the complement system is important to the pathogenesis of many non-immune complex mediated kidney diseases. In fact, in atypical hemolytic uremic syndrome and C3 glomerulopathy, uncontrolled complement activation is the primary driver of disease. Complement activation generates multiple pro-inflammatory fragments, and if not properly controlled it can cause fulminant tissue injury. Furthermore, the mechanisms of complement activation and complement-mediated injury vary from disease to disease. Many new drugs that target the complement cascade are in clinical development, so it is important to fully understand the biology of the complement system and its role in disease.
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18
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Complement Activation in Progression of Chronic Kidney Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:423-441. [PMID: 31399977 DOI: 10.1007/978-981-13-8871-2_20] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
Abstract
Chronic kidney disease (CKD) is a public health problem worldwide, with increasing incidence and prevalence. The mechanisms underlying the progression to end-stage renal disease (ESRD) is not fully understood. The complement system was traditionally regarded as an important part of innate immunity required for host protection against infection and for maintaining host hemostasis. However, compelling evidence from both clinical and experimental studies has strongly incriminated complement activation as a pivotal pathogenic mediator of the development of multiple renal diseases and progressive replacement of functioning nephrons by fibrosis. Both anaphylatoxins, i.e., C3a and C5a, and membrane attack complex (MAC) contribute to the damage that occurs during chronic renal progression through various mechanisms including direct proinflammatory and fibrogenic activity, chemotactic effect, activation of the renal renin-angiotensin system, and enhancement of T-cell immunity. Evolving understanding of the mechanisms of complement-mediated renal injury has led to the emergence of complement-targeting therapeutics. A variety of specific antibodies and inhibitors targeting complement components have shown efficacy in reducing disease in animal models. Moreover, building on these advances, targeting complement has gained encouraging success in treating patients with renal diseases such as atypical hemolytic uremic syndrome (aHUS). Nevertheless, it still requires a great deal of effort to develop inhibitors that can be applied to treat more patients effectively in routine clinical practice.
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19
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Guimarães FTL, Ferreira RN, Brito-Melo GEA, Rocha-Vieira E, Pereira WDF, Pinheiro SVB, Miranda AS, Simões E Silva AC. Pediatric Patients With Steroid-Sensitive Nephrotic Syndrome Have Higher Expression of T Regulatory Lymphocytes in Comparison to Steroid-Resistant Disease. Front Pediatr 2019; 7:114. [PMID: 31001501 PMCID: PMC6455073 DOI: 10.3389/fped.2019.00114] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/22/2018] [Accepted: 03/08/2019] [Indexed: 12/13/2022] Open
Abstract
Background and Aim: Idiopathic nephrotic syndrome (INS) is classified according to the response to drug therapy in steroid-sensitive (SS), steroid-dependent (SD), and steroid-resistant (SR) categories. Previous studies showed changes in inflammatory activity of subpopulations of lymphocytes in INS. This study aimed to compare SS and SR patients in regard to subpopulations of leukocytes, profile of regulatory lymphocytes, and migratory activity of lymphocyte subpopulations. Results obtained in INS patients were also compared to age and sex-matched healthy controls. Methods: This is a cross-sectional study including SS patients (n = 30), SR patients (n = 14), and controls (n = 10). Peripheral blood samples were withdrawn for ex-vivo leukocyte flow cytometry analysis. Results: Percentage of B-lymphocytes and natural killer (NK) cells were significantly reduced in SR patients when compared to controls, while the percentage of NKT cells were decreased in SS patients in comparison to controls. Percentages of CD4+ expressing FoxP3 and CTLA4 were significantly higher in SS patients in comparison to SR patients and controls. The expression of integrin CD18 on the surface of T lymphocytes (CD3+) was reduced in SS patients if compared to controls. Conclusion: This study found that SS INS patients have higher levels of regulatory T-lymphocytes and lower expression of adhesion molecules than SR patients.
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Affiliation(s)
- Fabio Tadeu Lourenço Guimarães
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gustavo Eustáquio Alvim Brito-Melo
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Etel Rocha-Vieira
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Wagner de Fátima Pereira
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Sérgio Veloso Brant Pinheiro
- Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ana Cristina Simões E Silva
- Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
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20
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Translational science in albuminuria: a new view of de novo albuminuria under chronic RAS suppression. Clin Sci (Lond) 2018; 132:739-758. [DOI: 10.1042/cs20180097] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2018] [Revised: 03/09/2018] [Accepted: 03/22/2018] [Indexed: 12/29/2022]
Abstract
The development of de novo albuminuria during chronic renin–angiotensin system (RAS) suppression is a clinical entity that remains poorly recognized in the biomedical literature. It represents a clear increment in global cardiovascular (CV) and renal risk that cannot be counteracted by RAS suppression. Although not specifically considered, it is clear that this entity is present in most published and ongoing trials dealing with the different forms of CV and renal disease. In this review, we focus on the mechanisms promoting albuminuria, and the predictors and new markers of de novo albuminuria, as well as the potential treatment options to counteract the excretion of albumin. The increase in risk that accompanies de novo albuminuria supports the search for early markers and predictors that will allow practising physicians to assess and prevent the development of de novo albuminuria in their patients.
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21
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Angeletti A, Reyes-Bahamonde J, Cravedi P, Campbell KN. Complement in Non-Antibody-Mediated Kidney Diseases. Front Med (Lausanne) 2017; 4:99. [PMID: 28748184 PMCID: PMC5506082 DOI: 10.3389/fmed.2017.00099] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2017] [Accepted: 06/21/2017] [Indexed: 12/15/2022] Open
Abstract
The complement system is part of the innate immune response that plays important roles in protecting the host from foreign pathogens. The complement components and relative fragment deposition have long been recognized to be strongly involved also in the pathogenesis of autoantibody-related kidney glomerulopathies, leading to direct glomerular injury and recruitment of infiltrating inflammation pathways. More recently, unregulated complement activation has been shown to be associated with progression of non-antibody-mediated kidney diseases, including focal segmental glomerulosclerosis, C3 glomerular disease, thrombotic microangiopathies, or general fibrosis generation in progressive chronic kidney diseases. Some of the specific mechanisms associated with complement activation in these diseases were recently clarified, showing a dominant role of alternative activation pathway. Over the last decade, a growing number of anticomplement agents have been developed, and some of them are being approved for clinical use or already in use. Therefore, anticomplement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Herein, we review the complement system activation, regulatory mechanisms, their involvement in non-antibody-mediated glomerular diseases, and the recent advances in complement-targeting agents as potential therapeutic strategies.
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Affiliation(s)
- Andrea Angeletti
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, St Orsola Hospital, University of Bologna, Bologna, Italy
| | - Joselyn Reyes-Bahamonde
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Paolo Cravedi
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kirk N Campbell
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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22
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Abstract
The role of complement (C) in the pathogenesis or progression of focal segmental glomerulosclerosis (FSGS) is uncertain. The present study assessed the relationship between serum C3, the baseline characteristics, and the progression of FSGS in the cohort and identified the clinical implications of serum C3 levels in patients with FSGS. Compared to the patients with C3 ≥ 85 mg/dL (N = 474), those with C3 < 85 mg/dL (N = 117) presented a higher level of serum creatinine, lower levels of eGFR, hemoglobin, proteinuria, triglyceride, cholesterol, IgA, as well as, severe tubulointerstitial injury (TI). Of the 221 patients with a mean follow-up of 53.3 months, the risk of reaching end-stage renal disease (ESRD) was significantly higher in patients with low serum C3 level (p < 0.001). An additional 40 patients with primary FSGS revealed a significant correlation between MAC and AP (p = 0.003), MAC and serum C3 (p = 0.018), and AP and serum C3 (p = 0.028). Compared to patients with none-to-mild TI, those with moderate-to-severe TI exhibited a lower level of serum C3 and AP, and a higher level of serum MAC. In conclusion, complement activation occurring in patients with FSGS is associated with clinical and histological severities. Low serum C3 was an independent risk factor for poor renal outcome in patients with FSGS.
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23
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Abstract
The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate immune responses. During C activation, circulating proteins are cleaved and nascent cleavage fragments participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our understanding of the benefits and limitations of C inhibition.
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Affiliation(s)
- Joshua M. Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado; and
| | - Carla M. Nester
- Stead Family Department of Pediatrics and
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa
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24
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Zhang YM, Gu QH, Huang J, Qu Z, Wang X, Meng LQ, Wang F, Liu G, Cui Z, Zhao MH. Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol 2016; 11:1582-1589. [PMID: 27340287 PMCID: PMC5012474 DOI: 10.2215/cjn.01190216] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/03/2016] [Accepted: 05/26/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Glomerular IgM deposition is commonly shown in primary FSGS and sometimes accompanied by C3 deposition. Clinical presentation and treatment outcomes of these patients are not investigated in detail. DESIGN, SETTING, PARTICIPANTS, &MEASUREMENTS One hundred six consecutive patients with biopsy-proven primary FSGS from 2004 to 2014 were enrolled retrospectively. Clinical features and treatment outcomes were compared between patients with and without IgM/C3 deposition. RESULTS Fifty-eight (54.7%) patients presented with IgM glomerular deposition on sclerotic segments. C3 and C1q depositions were shown exclusively in patients with IgM deposition (34.5% versus 0.0%; P<0.001 and 8.6% versus 0.0%; P=0.04, respectively). Patients with IgM deposition were younger (median; range: 24.5; 18.8-39.0 versus 46.5; 26.0-64.0 years old; P=0.001), had higher level of serum IgM (142.5; 96.3-206.0 versus 107.0; 71.0-140.0 mg/dl; P=0.01), and had higher level of eGFR (median; range 97.7; 48.0-135.8 versus 62.1; 33.7-93.9 ml/min per 1.73 m(2); P=0.01) at the time of kidney biopsy. The percentage of sclerosis lesions was significantly higher in patients with C3 deposition (median; range: 21.7%; 15.3%-31.1% versus 9.2%; 6.6%-20.0%; P=0.002). Although patients received comparable immunosuppressive treatments during 58.9 (29.5-81.1) months of follow-up, a significantly higher prevalence of refractory cases (no response or steroid dependent) occurred in patients with combined IgM and C3 deposition compared with patients with IgM deposition alone or without IgM deposition (58.8% versus 22.2% versus 15.6%, respectively; P=0.004). Multivariate analysis identified combined IgM and C3 deposition (odds ratio, 11.32; 95% confidence interval, 2.26 to 56.65; P=0.003) as an independent risk factor for refractory patients; 19 of 98 patients developed renal dysfunction when their serum creatinine levels increased >30% from baseline and reached >1.5 mg/dl. Combined IgM and C3 deposition (hazard ratio, 5.67; 95% confidence interval, 1.34 to 23.84; P=0.02) was identified as an independent risk factor for renal dysfunction. CONCLUSIONS Patients with primary FSGS and IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes, which indicate that IgM and C3 deposition might involve disease progression via complement activation.
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Affiliation(s)
- Yi-miao Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Qiu-hua Gu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Jing Huang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Zhen Qu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Xin Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Li-qiang Meng
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Fang Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Gang Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Zhao Cui
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
| | - Ming-hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China; and
- Peking-Tsinghua Center for Life Sciences, Beijing, China
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25
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Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis. Crit Care Med 2016; 44:e289-99. [PMID: 26757165 DOI: 10.1097/ccm.0000000000001566] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Toll-like receptors and complement are two components of the innate immunity. Complement factor B is essential for the alternative pathway of complement activation. We have recently reported that complement factor B is significantly up-regulated in the kidney and may contribute to acute tubular injury in an animal model of sepsis. This study investigates the mechanisms responsible for the complement factor B up-regulation and its role in sodium transporter expression in tubular cells during sepsis. DESIGN Animal study. SETTING Laboratory investigation. SUBJECTS C57BL/6 J wild-type, complement factor B(-/-), and Nfkb1(tm1Bal) p50(-/-) mice. INTERVENTIONS Human proximal tubular cells and mouse tubular epithelial cells were stimulated with Toll-like receptor agonists. Bay 11-7082 was used to block nuclear factor-κB pathway. Alternative pathway activation was detected by C3 zymosan deposition. Polymicrobial sepsis was created by cecal ligation and puncture. Sodium transporter gene expression was determined by quantitative reverse transcriptase-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS The agonists for Toll-like receptor 4 (lipopolysaccharide) or Toll-like receptor 3 (polyinosinic-polycytidylic acid) induced a marked increase in complement factor B expression in human proximal tubular cells and mouse tubular epithelial cells both at gene and protein levels. The Toll-like receptor 1/2 agonist, Pam3cys, induced complement factor B production only in human proximal tubular cells, not in mouse tubular epithelial cells. The Toll-like receptor 9 ligand, CpG oligodeoxynucleotides failed to induce complement factor B production either in human proximal tubular cells or in mouse tubular epithelial cells. Lipopolysaccharide/polyinosinic-polycytidylic acid-induced complement factor B up-regulation was blocked by Bay 11-7082, a potent inhibitor of nuclear factor-κB signaling, and in mouse tubular epithelial cells deficient in p50 subunit of nuclear factor-κB. Media from the lipopolysaccharide-treated mouse tubular epithelial cell cultures contained de novo synthesized complement factor B and led to functional alternative pathway activation. In a cecal ligation and puncture model, wild-type septic mice had down-regulated expression of sodium transporters in the kidney compared with the sham. In comparison, complement factor B mice or mice treated with anti-complement factor B displayed preserved levels of Na⁺/K⁺ ATPase-α1 following sepsis. CONCLUSIONS 1) Toll-like receptor 3/4 activation is sufficient to induce complement factor B production via nuclear factor-κB pathway and to enhance alternative pathway activation in the kidney tubular epithelial cells. 2) Complement factor B may contribute to the down-regulation of certain sodium transporter expression during sepsis.
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26
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Morigi M, Locatelli M, Rota C, Buelli S, Corna D, Rizzo P, Abbate M, Conti D, Perico L, Longaretti L, Benigni A, Zoja C, Remuzzi G. A previously unrecognized role of C3a in proteinuric progressive nephropathy. Sci Rep 2016; 6:28445. [PMID: 27345360 PMCID: PMC4921969 DOI: 10.1038/srep28445] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/16/2016] [Accepted: 06/02/2016] [Indexed: 12/16/2022] Open
Abstract
Podocyte loss is the initial event in the development of glomerulosclerosis, the structural hallmark of progressive proteinuric nephropathies. Understanding mechanisms underlying glomerular injury is the key challenge for identifying novel therapeutic targets. In mice with protein-overload induced by bovine serum albumin (BSA), we evaluated whether the alternative pathway (AP) of complement mediated podocyte depletion and podocyte-dependent parietal epithelial cell (PEC) activation causing glomerulosclerosis. Factor H (Cfh−/−) or factor B-deficient mice were studied in comparison with wild-type (WT) littermates. WT+BSA mice showed podocyte depletion accompanied by glomerular complement C3 and C3a deposits, PEC migration to capillary tuft, proliferation, and glomerulosclerosis. These changes were more prominent in Cfh−/− +BSA mice. The pathogenic role of AP was documented by data that factor B deficiency preserved glomerular integrity. In protein-overload mice, PEC dysregulation was associated with upregulation of CXCR4 and GDNF/c-Ret axis. In vitro studies provided additional evidence of a direct action of C3a on proliferation and CXCR4-related migration of PECs. These effects were enhanced by podocyte-derived GDNF. In patients with proteinuric nephropathy, glomerular C3/C3a paralleled PEC activation, CXCR4 and GDNF upregulation. These results indicate that mechanistically uncontrolled AP complement activation is not dispensable for podocyte-dependent PEC activation resulting in glomerulosclerosis.
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Affiliation(s)
- Marina Morigi
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Monica Locatelli
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Cinzia Rota
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Simona Buelli
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Daniela Corna
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Paola Rizzo
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Mauro Abbate
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Debora Conti
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Luca Perico
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Lorena Longaretti
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Ariela Benigni
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Carlamaria Zoja
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.,Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.,Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
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27
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Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury. Kidney Int 2016; 90:109-22. [PMID: 27165610 DOI: 10.1016/j.kint.2016.02.036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/12/2015] [Revised: 02/23/2016] [Accepted: 02/25/2016] [Indexed: 12/29/2022]
Abstract
Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location.
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28
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Vernon KA, Ruseva MM, Cook HT, Botto M, Malik TH, Pickering MC. Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy. J Am Soc Nephrol 2016; 27:1334-42. [PMID: 26374608 PMCID: PMC4849824 DOI: 10.1681/asn.2015030295] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/18/2015] [Accepted: 07/28/2015] [Indexed: 11/03/2022] Open
Abstract
The complement-mediated renal diseases C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abnormalities in the regulation of the complement alternative pathway (AP). The major negative regulator of the AP is the plasma protein complement factor H (FH). Abnormalities in FH result in uncontrolled activation of C3 through the AP and associate with susceptibility to both C3G and aHUS. Although previously developed FH-deficient animal models have provided important insights into the mechanisms underlying susceptibility to these unique phenotypes, these models do not entirely reproduce the clinical observations. FH is predominantly synthesized in the liver. We generated mice with hepatocyte-specific FH deficiency and showed that these animals have reduced plasma FH levels with secondary reduction in plasma C3. Unlike mice with complete FH deficiency, hepatocyte-specific FH-deficient animals developed neither plasma C5 depletion nor accumulation of C3 along the glomerular basement membrane. In contrast, subtotal FH deficiency associated with mesangial C3 accumulation consistent with C3G. Although there was no evidence of spontaneous thrombotic microangiopathy, the hepatocyte-specific FH-deficient animals developed severe C5-dependent thrombotic microangiopathy after induction of complement activation within the kidney by accelerated serum nephrotoxic nephritis. Taken together, our data indicate that subtotal FH deficiency can give rise to either spontaneous C3G or aHUS after a complement-activating trigger within the kidney and that the latter is C5 dependent.
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Affiliation(s)
- Katherine A Vernon
- Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
| | - Marieta M Ruseva
- Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
| | - H Terence Cook
- Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
| | - Marina Botto
- Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
| | - Talat H Malik
- Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
| | - Matthew C Pickering
- Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
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29
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Renner B, Tong HH, Laskowski J, Jonscher K, Goetz L, Woolaver R, Hannan J, Li YX, Hourcade D, Pickering MC, Holers VM, Thurman JM. Annexin A2 Enhances Complement Activation by Inhibiting Factor H. THE JOURNAL OF IMMUNOLOGY 2016; 196:1355-65. [PMID: 26729803 DOI: 10.4049/jimmunol.1500793] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 04/06/2015] [Accepted: 11/27/2015] [Indexed: 12/31/2022]
Abstract
Factor H is a circulating protein that regulates activation of the alternative pathway (AP) of complement. Mutations and genetic variations of factor H are associated with several AP-mediated diseases, highlighting the critical role of factor H in AP regulation. AP-mediated inflammation is typically triggered by illness or tissue injury, however, and tissue injury can trigger AP activation in individuals with fully functional factor H. This suggests that factor H function is affected by local conditions within tissues. We hypothesized that inducible proteins impair the ability of factor H to locally control the AP, thereby increasing AP activation. We used purified murine factor H to immunoprecipitate binding partners from mouse kidneys. Using immunoaffinity liquid chromatography-mass spectrometry, we identified annexin A2 as a factor H binding partner. Further experiments showed that annexin A2 reduces the binding of factor H to cell surfaces. Recombinant annexin A2 impaired complement regulation by factor H and increased complement activation on renal cell surfaces in vitro and in vivo. In a murine model of acute pneumococcal otitis media, the administration of annexin A2 increased AP-mediated bacterial opsonization and clearance. In conclusion, the local production of annexin A2 within tissues suppresses regulation of the AP by factor H. Annexin A2 can contribute to AP-mediated tissue inflammation by locally impairing factor H function, but it can also improve complement-mediated bacterial clearance.
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Affiliation(s)
- Brandon Renner
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Hua Hua Tong
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210
| | - Jennifer Laskowski
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Karen Jonscher
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Lindsey Goetz
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Rachel Woolaver
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Jonathan Hannan
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Yong Xing Li
- Department of Otolaryngology, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210
| | - Dennis Hourcade
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and
| | - Matthew C Pickering
- Centre for Complement and Inflammation Research, South Kensington Campus, Imperial College, London SW7 2AZ, United Kingdom
| | - V Michael Holers
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Joshua M Thurman
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
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30
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Thurman JM, Wong M, Renner B, Frazer-Abel A, Giclas PC, Joy MS, Jalal D, Radeva MK, Gassman J, Gipson DS, Kaskel F, Friedman A, Trachtman H. Complement Activation in Patients with Focal Segmental Glomerulosclerosis. PLoS One 2015; 10:e0136558. [PMID: 26335102 PMCID: PMC4559462 DOI: 10.1371/journal.pone.0136558] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/27/2015] [Accepted: 08/05/2015] [Indexed: 01/19/2023] Open
Abstract
Background Recent pre-clinical studies have shown that complement activation contributes to glomerular and tubular injury in experimental FSGS. Although complement proteins are detected in the glomeruli of some patients with FSGS, it is not known whether this is due to complement activation or whether the proteins are simply trapped in sclerotic glomeruli. We measured complement activation fragments in the plasma and urine of patients with primary FSGS to determine whether complement activation is part of the disease process. Study Design Plasma and urine samples from patients with biopsy-proven FSGS who participated in the FSGS Clinical Trial were analyzed. Setting and Participants We identified 19 patients for whom samples were available from weeks 0, 26, 52 and 78. The results for these FSGS patients were compared to results in samples from 10 healthy controls, 10 patients with chronic kidney disease (CKD), 20 patients with vasculitis, and 23 patients with lupus nephritis. Outcomes Longitudinal control of proteinuria and estimated glomerular filtration rate (eGFR). Measurements Levels of the complement fragments Ba, Bb, C4a, and sC5b-9 in plasma and urine. Results Plasma and urine Ba, C4a, sC5b-9 were significantly higher in FSGS patients at the time of diagnosis than in the control groups. Plasma Ba levels inversely correlated with the eGFR at the time of diagnosis and at the end of the study. Plasma and urine Ba levels at the end of the study positively correlated with the level of proteinuria, the primary outcome of the study. Limitations Limited number of patients with samples from all time-points. Conclusions The complement system is activated in patients with primary FSGS, and elevated levels of plasma Ba correlate with more severe disease. Measurement of complement fragments may identify a subset of patients in whom the complement system is activated. Further investigations are needed to confirm our findings and to determine the prognostic significance of complement activation in patients with FSGS.
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Affiliation(s)
- Joshua M. Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Maria Wong
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Brandon Renner
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Ashley Frazer-Abel
- Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America
| | - Patricia C. Giclas
- Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America
| | - Melanie S. Joy
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Diana Jalal
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Milena K. Radeva
- Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Jennifer Gassman
- Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Debbie S. Gipson
- Department of Pediatrics, CS Mott Children’s Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Frederick Kaskel
- Department of Pediatrics, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Aaron Friedman
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Howard Trachtman
- Department of Pediatrics, NYU Langone Medical Center, NYU School of Medicine, New York, New York, United States of America
- * E-mail:
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Cho H. Complement regulation: physiology and disease relevance. KOREAN JOURNAL OF PEDIATRICS 2015; 58:239-44. [PMID: 26300937 PMCID: PMC4543182 DOI: 10.3345/kjp.2015.58.7.239] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 04/28/2015] [Accepted: 05/27/2015] [Indexed: 01/21/2023]
Abstract
The complement system is part of the innate immune response and as such defends against invading pathogens, removes immune complexes and damaged self-cells, aids organ regeneration, confers neuroprotection, and engages with the adaptive immune response via T and B cells. Complement activation can either benefit or harm the host organism; thus, the complement system must maintain a balance between activation on foreign or modified self surfaces and inhibition on intact host cells. Complement regulators are essential for maintaining this balance and are classified as soluble regulators, such as factor H, and membrane-bound regulators. Defective complement regulators can damage the host cell and result in the accumulation of immunological debris. Moreover, defective regulators are associated with several autoimmune diseases such as atypical hemolytic uremic syndrome, dense deposit disease, age-related macular degeneration, and systemic lupus erythematosus. Therefore, understanding the molecular mechanisms by which the complement system is regulated is important for the development of novel therapies for complement-associated diseases.
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Affiliation(s)
- Heeyeon Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Lieberman LA, Mizui M, Nalbandian A, Bossé R, Crispín JC, Tsokos GC. Complement receptor of the immunoglobulin superfamily reduces murine lupus nephritis and cutaneous disease. Clin Immunol 2015; 160:286-91. [PMID: 25988858 DOI: 10.1016/j.clim.2015.05.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/28/2015] [Revised: 04/28/2015] [Accepted: 05/07/2015] [Indexed: 10/23/2022]
Abstract
Complement activation takes place in autoimmune diseases and accounts for tissue inflammation. Previously, complement inhibition has been considered for the treatment of SLE. Complement receptor of the immunoglobulin superfamily (CRIg) is a selective inhibitor of the alternative pathway of complement and a soluble form reverses established inflammation and bone destruction in experimental autoimmune arthritis. We asked whether specific inhibition of the alternative pathway could inhibit autoimmunity and/or organ damage in lupus-prone mice. Accordingly, we treated lupus-prone MRL/lpr mice with a soluble form of CRIg (CRIg-Fc) and we found that it significantly diminished skin lesions, proteinuria and pyuria, and kidney pathology. Interestingly, serum levels of anti-DNA antibodies were not affected despite the fact that serum complement 3 (C3) levels increased significantly. Immunofluorescent staining of kidney tissues revealed a reduction in staining intensity for C3, IgG, and the macrophage marker Mac-2. Thus our data show that inhibition of the alternative pathway of complement controls skin and kidney inflammation even in the absence of an effect on the production of autoantibodies. We propose that CRIg should be considered for clinical trials in patients with systemic lupus erythematosus.
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Affiliation(s)
- Linda A Lieberman
- Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Masayuki Mizui
- Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Angèle Nalbandian
- Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Robin Bossé
- Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - José C Crispín
- Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - George C Tsokos
- Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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The experimental model of nephrotic syndrome induced by Doxorubicin in rodents: an update. Inflamm Res 2015; 64:287-301. [DOI: 10.1007/s00011-015-0813-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/27/2014] [Revised: 02/24/2015] [Accepted: 03/05/2015] [Indexed: 12/18/2022] Open
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Fearn A, Sheerin NS. Complement activation in progressive renal disease. World J Nephrol 2015; 4:31-40. [PMID: 25664245 PMCID: PMC4317626 DOI: 10.5527/wjn.v4.i1.31] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/02/2014] [Revised: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic non-resolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in pre-clinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomerulonephritis, thrombotic microangiopathies and transplant rejection. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease.
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Abstract
Genetic or autoimmune defects that lead to dysregulation of the alternative pathway of complement have been associated with the development of atypical haemolytic uraemic syndrome (aHUS), which is characterized by thrombocytopenia, haemolytic anaemia and acute kidney injury. The relationship between aHUS, podocyte dysfunction and the resultant proteinuria has not been adequately investigated. However, the report of mutations in diacylglycerol kinase ε (DGKE) as a cause of recessive infantile aHUS characterized by proteinuria, highlighted podocyte dysfunction as a potential complication of aHUS. DGKE deficiency was originally thought to trigger aHUS through pathogenetic mechanisms distinct from complement dysregulation; however, emerging findings suggest an interplay between DGKE and complement systems. Podocyte dysfunction with nephrotic-range proteinuria can also occur in forms of aHUS associated with genetic or autoimmune complement dysregulation without evidence of DGKE mutations. Furthermore, proteinuric glomerulonephritides can be complicated by aHUS, possibly as a consequence of podocyte dysfunction inducing endothelial injury and prothrombotic abnormalities.
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Affiliation(s)
- Marina Noris
- IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò", Via Camozzi 3, 24020, Ranica, Bergamo, Italy
| | - Caterina Mele
- IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò", Via Camozzi 3, 24020, Ranica, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò", Via Camozzi 3, 24020, Ranica, Bergamo, Italy
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Fuquay R, Renner B, Kulik L, McCullough JW, Amura C, Strassheim D, Pelanda R, Torres R, Thurman JM. Renal ischemia-reperfusion injury amplifies the humoral immune response. J Am Soc Nephrol 2013; 24:1063-72. [PMID: 23641055 DOI: 10.1681/asn.2012060560] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/27/2023] Open
Abstract
Renal transplant recipients who experience delayed graft function have increased risks of rejection and long-term graft failure. Ischemic damage is the most common cause of delayed graft function, and although it is known that tissue inflammation accompanies renal ischemia, it is unknown whether renal ischemia affects the production of antibodies by B lymphocytes, which may lead to chronic humoral rejection and allograft failure. Here, mice immunized with a foreign antigen 24-96 hours after renal ischemia-reperfusion injury developed increased levels of antigen-specific IgG1 compared with sham-treated controls. This amplified IgG1 response did not follow unilateral ischemia, and it did not occur in response to a T-independent antigen. To test whether innate immune activation in the kidney after ischemia affects the systemic immune response to antigen, we repeated the immunization experiment using mice deficient in factor B that lack a functional alternative pathway of complement. Renal ischemia-reperfusion injury did not cause amplification of the antigen-specific antibodies in these mice, suggesting that the increased immune response requires a functional alternative pathway of complement. Taken together, these data suggest that ischemic renal injury leads to a rise in antibody production, which may be harmful to renal allografts, possibly explaining a mechanism underlying the link between delayed graft function and long-term allograft failure.
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Affiliation(s)
- Richard Fuquay
- Division of Renal Disease and Hypertension, University of Colorado Denver Health Science Center, Aurora, Colorado 80045, USA
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Strassheim D, Renner B, Panzer S, Fuquay R, Kulik L, Ljubanović D, Holers VM, Thurman JM. IgM contributes to glomerular injury in FSGS. J Am Soc Nephrol 2013; 24:393-406. [PMID: 23393315 DOI: 10.1681/asn.2012020187] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/03/2022] Open
Abstract
Glomerular IgM and C3 deposits frequently accompany idiopathic FSGS and secondary glomerulosclerosis, but it is unknown whether IgM activates complement, possibly contributing to the pathogenesis of these diseases. We hypothesized that IgM natural antibody binds to neoepitopes exposed in the glomerulus after nonimmune insults, triggering activation of the complement system and further injury. We examined the effects of depleting B cells, using three different strategies, on adriamycin-induced glomerulosclerosis. First, we treated wild-type mice with an anti-murine CD20 antibody, which depletes B cells, before disease induction. Second, we evaluated adriamycin-induced glomerulosclerosis in Jh mice, a strain that lacks mature B cells. Third, we locally depleted peritoneal B cells via hypotonic shock before disease induction. All three strategies reduced deposition of IgM in the glomerulus after administration of adriamycin and attenuated the development of albuminuria. Furthermore, we found that glomerular IgM and C3 were detectable in a subset of patients with FSGS; C3 was present as an activation fragment and colocalized with glomerular IgM, suggesting that glomerular IgM may have bound a cognate ligand. Taken together, these results suggest that IgM activates the complement system within the glomerulus in an animal model of glomerulosclerosis. Strategies that reduce IgM natural antibody or that prevent complement activation may slow the progression of glomerulosclerosis.
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Affiliation(s)
- Derek Strassheim
- Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA
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Zaferani A, Vivès RR, van der Pol P, Navis GJ, Daha MR, van Kooten C, Lortat-Jacob H, Seelen MA, van den Born J. Factor h and properdin recognize different epitopes on renal tubular epithelial heparan sulfate. J Biol Chem 2012; 287:31471-81. [PMID: 22815489 DOI: 10.1074/jbc.m112.380386] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022] Open
Abstract
During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (K(D) values of 32 and 93 nm, respectively). Using a library of HS-like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement-derived tubular injury in proteinuric renal diseases.
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Affiliation(s)
- Azadeh Zaferani
- Department of Nephrology, University Medical Center, 9713 GZ Groningen, The Netherlands.
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Abstract
Numerous renal diseases are characterized by complement activation within the kidney, and several lines of evidence implicate complement activation as an important part of the pathogenesis of these diseases. Investigators have long anticipated that complement inhibitors would be important and effective therapies for renal diseases. Eculizumab is a monoclonal antibody to the complement protein C5 that has now been administered to patients with several types of renal disease. The apparent efficacy of this agent may herald a new era in the treatment of renal disease, but many questions about the optimal use of therapeutic complement inhibitors remain. Herein we review the rationale for using complement inhibitors in patients with renal disease and discuss several drugs and approaches that are currently under development.
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40
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Thurman JM, Tchepeleva SN, Haas M, Panzer S, Boackle SA, Glogowska MJ, Quigg RJ, Holers VM. Complement alternative pathway activation in the autologous phase of nephrotoxic serum nephritis. Am J Physiol Renal Physiol 2012; 302:F1529-36. [PMID: 22492944 DOI: 10.1152/ajprenal.00422.2011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022] Open
Abstract
The complement cascade is an important part of the innate immune system, but pathological activation of this system causes tissue injury in several autoimmune and inflammatory diseases, including immune complex glomerulonephritis. We examined whether mice with targeted deletion of the gene for factor B (fB(-/-) mice) and selective deficiency in the alternative pathway of complement are protected from injury in the nephrotoxic serum (NTS) nephritis model of antibody-mediated glomerulonephritis. When the acute affects of the anti-glomerular basement membrane antibody were assessed, fB(-/-) mice developed a degree of injury similar to wild-type controls. If the mice were presensitized with sheep IgG or if the mice were followed for 5 mo postinjection, however, the fB(-/-) mice developed milder injury than wild-type mice. The immune response of fB(-/-) mice exposed to sheep IgG was similar to that of wild-type mice, but the fB(-/-) mice had less glomerular C3 deposition and lower levels of albuminuria. These results demonstrate that fB(-/-) mice are not significantly protected from acute heterologous injury in NTS nephritis but are protected from autologous injury in response to a planted glomerular antigen. Thus, although the glomerulus is resistant to antibody-initiated, alternative pathway-mediated injury, inhibition of this complement pathway may be beneficial in chronic immune complex-mediated diseases.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
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41
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Vernon KA, Cook HT. Complement in glomerular disease. Adv Chronic Kidney Dis 2012; 19:84-92. [PMID: 22449345 DOI: 10.1053/j.ackd.2012.02.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/13/2011] [Revised: 02/16/2012] [Accepted: 02/23/2012] [Indexed: 01/14/2023]
Abstract
The role of the complement system in renal disease has long been recognized, but there have been major advances in our understanding of its role over the past decade. Complement plays a critical role not only in host's defense against infection and preventing damage to "self" tissues but also mediates tissue injury, both in the glomerulus and tubulointerstitium. Although injury may originate in the glomerulus, resulting proteinuria and complement activation within the tubular lumen may lead to tubulointerstitial damage and progressive renal disease. Recent advances in our understanding of the mechanisms by which complement mediates renal injury have led to the development of promising strategies with which complement may be targeted to prevent renal injury and its associated complications.
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Abstract
Systemic lupus erythematosus is a prototypic autoimmune disease characterized by autoantibody production and immune complex formation/deposition in target organs such as the kidney. Resultant local inflammation then leads to organ damage. Nephritis, a major cause of morbidity and mortality in patients with lupus, occurs in approximately 50% of lupus patients. In the present review, we provide an overview of the current research and knowledge concerning mechanisms of renal injury in both lupus-prone mouse models and human lupus patients.
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43
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Matheis KA, Com E, Gautier JC, Guerreiro N, Brandenburg A, Gmuender H, Sposny A, Hewitt P, Amberg A, Boernsen O, Riefke B, Hoffmann D, Mally A, Kalkuhl A, Suter L, Dieterle F, Staedtler F. Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers. Toxicol Appl Pharmacol 2010; 252:112-22. [PMID: 21081137 DOI: 10.1016/j.taap.2010.11.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/10/2010] [Revised: 10/15/2010] [Accepted: 11/09/2010] [Indexed: 11/18/2022]
Abstract
The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with "omics" data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.
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Affiliation(s)
- Katja A Matheis
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
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44
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Brideau G, Doucet A. Over-expression of adenosine deaminase in mouse podocytes does not reverse puromycin aminonucleoside resistance. BMC Nephrol 2010; 11:15. [PMID: 20649959 PMCID: PMC2915970 DOI: 10.1186/1471-2369-11-15] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/09/2010] [Accepted: 07/22/2010] [Indexed: 12/02/2022] Open
Abstract
Background Edema in nephrotic syndrome results from renal retention of sodium and alteration of the permeability properties of capillaries. Nephrotic syndrome induced by puromycin aminonucleoside (PAN) in rats reproduces the biological and clinical signs of the human disease, and has been widely used to identify the cellular mechanisms of sodium retention. Unfortunately, mice do not develop nephrotic syndrome in response to PAN, and we still lack a good mouse model of the disease in which the genetic tools necessary for further characterizing the pathophysiological pathway could be used. Mouse resistance to PAN has been attributed to a defect in glomerular adenosine deaminase (ADA), which metabolizes PAN. We therefore attempted to develop a mouse line sensitive to PAN through induction of normal adenosine metabolism in their podocytes. Methods A mouse line expressing functional ADA under the control of the podocyte-specific podocin promoter was generated by transgenesis. The effect of PAN on urinary excretion of sodium and proteins was compared in rats and in mice over-expressing ADA and in littermates. Results We confirmed that expression of ADA mRNAs was much lower in wild type mouse than in rat glomerulus. Transgenic mice expressed ADA specifically in the glomerulus, and their ADA activity was of the same order of magnitude as in rats. Nonetheless, ADA transgenic mice remained insensitive to PAN treatment in terms of both proteinuria and sodium retention. Conclusions Along with previous results, this study shows that adenosine deaminase is necessary but not sufficient to confer PAN sensitivity to podocytes. ADA transgenic mice could be used as a background strain for further transgenesis.
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Affiliation(s)
- Gaëlle Brideau
- Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale, Centre National de Recherche Scientifique, Paris, France
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45
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Tang Z, Sheerin N. Complement Activation and Progression of Chronic Kidney Disease. Int J Organ Transplant Med 2009. [DOI: 10.1016/s1561-5413(09)60241-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/20/2022] Open
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46
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Paixão-Cavalcante D, Hanson S, Botto M, Cook HT, Pickering MC. Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase. Mol Immunol 2009; 46:1942-50. [PMID: 19411110 PMCID: PMC2697322 DOI: 10.1016/j.molimm.2009.03.030] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/16/2009] [Accepted: 03/20/2009] [Indexed: 12/22/2022]
Abstract
Dense deposit disease (DDD) is strongly associated with the uncontrolled activation of the complement alternative pathway. Factor H (CFH)-deficient (Cfh−/−) mice spontaneously develop C3 deposition along the glomerular basement membrane (GBM) with subsequent development of glomerulonephritis with features of DDD, a lesion dependent on C3 activation. In order to understand the role of CFH in preventing renal damage associated with the dysregulation of the alternative pathway we administered purified mouse CFH (mCFH) to Cfh−/− mice. 24 h following the administration of mCFH we observed an increase in plasma C3 levels with presence of intact C3 in circulation showing that mCFH restored control of C3 activation in fluid phase. mCFH resulted in the reduction of iC3b deposition along the GBM. The exogenous mCFH was readily detectable in plasma but critically not in association with C3 along the GBM. Thus, the reduction in GBM C3 was dependent on the ability of mCFH to regulate C3 activation in plasma. Western blot analysis of glomeruli from Cfh−/− mice demonstrated the presence of iC3b. Our data show that the C3 along the GBM in Cfh−/− mice is the C3 fragment iC3b and that this is derived from plasma C3 activation. The implication is that successful therapy of DDD is likely to be achieved by therapies that inhibit C3 turnover in plasma.
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Affiliation(s)
- Danielle Paixão-Cavalcante
- Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - Steven Hanson
- Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - Marina Botto
- Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - H. Terence Cook
- Department of Histopathology, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - Matthew C. Pickering
- Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
- Corresponding author. Tel.: +44 208 383 2398; fax: +44 208 383 2379.
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47
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Pippin JW, Brinkkoetter PT, Cormack-Aboud FC, Durvasula RV, Hauser PV, Kowalewska J, Krofft RD, Logar CM, Marshall CB, Ohse T, Shankland SJ. Inducible rodent models of acquired podocyte diseases. Am J Physiol Renal Physiol 2009; 296:F213-29. [DOI: 10.1152/ajprenal.90421.2008] [Citation(s) in RCA: 198] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022] Open
Abstract
Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases. Rodents have been extensively used experimentally to better define mechanisms of disease induction and progression, as well as to identify potential targets and therapies. The development of podocyte-specific genetically modified mice has energized the research field to better understand which animal models are appropriate to study acquired podocyte diseases. In this review we discuss inducible experimental models of acquired nondiabetic podocyte diseases in rodents, namely, passive Heymann nephritis, puromycin aminonucleoside nephrosis, adriamycin nephrosis, liopolysaccharide, crescentic glomerulonephritis, and protein overload nephropathy models. Details are given on the model backgrounds, how to induce each model, the interpretations of the data, and the benefits and shortcomings of each. Genetic rodent models of podocyte injury are excluded.
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48
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Tang Z, Lu B, Hatch E, Sacks SH, Sheerin NS. C3a mediates epithelial-to-mesenchymal transition in proteinuric nephropathy. J Am Soc Nephrol 2009; 20:593-603. [PMID: 19158354 DOI: 10.1681/asn.2008040434] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022] Open
Abstract
Tubulointerstitial inflammation and progressive fibrosis are common pathways that lead to kidney failure in proteinuric nephropathies. Activation of the complement system has been implicated in the development of tubulointerstitial injury in clinical and animal studies, but the mechanism by which complement induces kidney injury is not fully understood. Here, we studied the effect of complement on the phenotype of tubular epithelial cells. Tubular epithelial cells exposed to serum proteins adopted phenotypic and functional characteristics of mesenchymal cells. Expression of E-cadherin protein decreased and expression of both alpha-smooth muscle actin protein and collagen I mRNA increased. Exposure of the cells to the complement anaphylotoxin C3a induced similar features. Treating with a C3a receptor (C3aR) antagonist prevented both C3a- and serum-induced epithelial-to-mesenchymal transition. In the adriamycin-induced proteinuria model, C3aR-deficient mice demonstrated less injury, preserved renal function, and improved survival compared with wild-type mice. Furthermore, the kidneys of C3aR-deficient mice had significantly less interstitial collagen I and alpha-smooth muscle actin. In summary, the complement anaphylotoxin C3a is an important mediator of glomerular and tubulointerstitial injury and can induce tubular epithelial-to-mesenchymal transition.
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Affiliation(s)
- Ziyong Tang
- King's College London, Department of Nephrology and Transplantation, Guy's Hospital London, London, UK
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