Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease

Herrera, Marcela; Söderberg, Magnus; Sabirsh, Alan; Valastro, Barbara; Mölne, Johan; Santamaría, Beatriz; Valverde, Ángela M.; Guionaud, Silvia; Heasman, Stephanie; Bigley, Alison; Jermutus, Lutz; Rondinone, Cristina M.; Coghlan, Matthew P.; Baker, David R.; Quinn, Carol Moreno

doi:10.1152/ajprenal.00179.2016

Cited by 26 publications

(26 citation statements)

References 47 publications

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“…Increased renal T-cell recruitment were detected both in patients with DN and diabetic mice 31. A series of investigations inhibiting T-cell activation or targeting Th17 ameliorated diabetic renal damage in animal models 32–35. In our study, we found the T-cell immune response was suppressed in C3aR −/− diabetic mice compared with WT diabetic mice by microarray, indicating a link between C3a and T-cell adaptive immunity in DN.…”

Section: Discussionsupporting

confidence: 49%

Deficiency of C3a receptor attenuates the development of diabetic nephropathy

Chang

Chen

et al. 2019

BMJ Open Diab Res Care

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ObjectiveDiabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN.Research design and methodsThe expression of C3aR was examined in the renal specimen of patients with DN. Using a C3aR gene knockout mice (C3aR−/−), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a.ResultsCompared with normal controls, the renal expression of C3aR was significantly increased in patients with DN. C3aR−/− diabetic mice developed less severe diabetic renal damage compared with wild-type (WT) diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T-cell adaptive immunity in C3aR−/− diabetic mice compared with WT diabetic mice, and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophage infiltration. In vitro study demonstrated C3a can enhance macrophage-secreted cytokines which could induce inflammatory responses and differentiation of T-cell lineage.ConclusionsC3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T-cell adaptive immunity, possibly by influencing macrophage-secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.

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Section: Discussionsupporting

confidence: 49%

Deficiency of C3a receptor attenuates the development of diabetic nephropathy

Chang

Chen

et al. 2019

BMJ Open Diab Res Care

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“…In the same line, induction of DN in mice without T and B lymphocytes (Rag1-/-mice) showed that lymphocytes activate glomerular macrophages, induce podocyte injury, and increase albuminuria [59]. Pharmacological inhibition of T-cell activation with CTLA4-Fc abatacept also reduced albuminuria in mice with DN [60].…”

Section: T Lymphocytesmentioning

confidence: 94%

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Rayego‐Mateos

Morgado‐Pascual

Opazo-Ríos

et al. 2020

IJMS

175

127

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Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

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“…Importantly, infiltration of immune cells is a key feature of DN [17]. Activated T cells (CD4+ and CD8+) are mainly located in the renal interstitium of diabetic kidneys [44][45][46]. Although CD4+ IL-17+ cells are the main source of IL-17A production, other cells, including macrophages, neutrophils, natural killer, dendritic, and mast cells, have also been described to produce this cytokine.…”

Section: Il-17 In Human Diabetic Nephropathymentioning

confidence: 99%

Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

Lavoz

Rayego‐Mateos

Orejudo

et al. 2020

JCM

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Chronic kidney disease has become a major medical issue in recent years due to its high prevalence worldwide, its association with premature mortality, and its social and economic implications. A number of patients gradually progress to end-stage renal disease (ESRD), requiring then dialysis and kidney transplantation. Currently, approximately 40% of patients with diabetes develop kidney disease, making it the most prevalent cause of ESRD. Thus, more effective therapies for diabetic nephropathy are needed. In preclinical studies of diabetes, anti-inflammatory therapeutic strategies have been used to protect the kidneys. Recent evidence supports that immune cells play an active role in the pathogenesis of diabetic nephropathy. Th17 immune cells and their effector cytokine IL-17A have recently emerged as promising targets in several clinical conditions, including renal diseases. Here, we review current knowledge regarding the involvement of Th17/IL-17A in the genesis of diabetic renal injury, as well as the rationale behind targeting IL-17A as an additional therapy in patients with diabetic nephropathy.

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Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease

Cited by 26 publications

References 47 publications

Deficiency of C3a receptor attenuates the development of diabetic nephropathy

Deficiency of C3a receptor attenuates the development of diabetic nephropathy

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

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