Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia

Zhang, Qiong; Huang, Yu; Zhang, Keke; Huang, Yanjun; Yan, Yan; Fan, Wei; Wu, Jie; Wang, Xiao; Xu, Zhangye; Chen, Yongtao; Cheng, Xue; Yong, Li; Jiao, Jinyu; Ye, Duyun

doi:10.1016/j.envpol.2016.07.073

Cited by 45 publications

(27 citation statements)

References 44 publications

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“…In animal models, Cd triggers excessive complement activation by induction of complement component C3, the key element of the complement system (38,39). Activated C3 is cleaved to create C3a and C3b, the latter of which binds to the surface of pathogens or other target cells (11).…”

Section: Discussionmentioning

confidence: 99%

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Chen

Liu

et al. 2019

The Journal of Immunology

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Cadmium (Cd) is an environmental toxin that induces nephrotoxicity. Complement factor H (CFH), an inhibitor of complement activation, is involved in the pathogenesis of various renal diseases. In this study, we investigated the effects of Cd on CFH production by the kidney. In C57B6/J mice, an increased CFH level was found in renal blood and glomerular endothelial cells after Cd treatment. In vitro, Cd induces an increased CFH secretion and mRNA expression in human renal glomerular endothelial cells but not in human podocytes or human mesangial cells. Cd activates the JNK pathway and increases c-Jun and c-Fos in human renal glomerular endothelial cells. A JNK inhibitor, SP600125, specifically abolishes Cd-induced CFH production. By chromatin immunoprecipitation assay and EMSA, the −1635 AP-1 motif on human CFH promoter was identified as the binding element for c-Jun and c-Fos. In a luciferase activity assay, mutation of the AP1 site eliminates Cd-induced increase of CFH promoter activity. Thus, the −1635 AP-1 motif on the CFH promoter region mediates Cd-inducible CFH gene expression.

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Section: Discussionmentioning

confidence: 99%

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Chen

Liu

et al. 2019

The Journal of Immunology

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“…The causes could be genetic, modifications in the vascular endothelium induced by lifestyle factors, or immunological disorders [ 83 ]. Using in vivo models, Cd exposure has been associated to preeclampsia development with increased systolic pressure and proteinuria [ 72 , 73 , 74 ]. The mechanisms suggested for preeclampsia induction by Cd exposure are: placental damage caused by oxidative DNA damage [ 65 , 72 ], and high levels of corticosterone in plasma, consequence of placental alterations (downregulation of 11β-hydroxysteroid dehydrogenase, 11β-HSD2) [ 73 , 75 ].…”

Section: Toxic Effects In Damsmentioning

confidence: 99%

“…Other mechanisms possibly related to the development of preeclampsia are immunological disorders. Zhang et al observed an increased activation of complement component 5 (C5) in preeclamptic patients, determined by the increase in the concentration of the fragment C5 (C5a) in blood samples, which is a marker for complement activation [ 74 ]. The complement activation has been considered to be partially responsible for the development of preeclampsia and kidney injury [ 84 ].…”

Section: Toxic Effects In Damsmentioning

confidence: 99%

Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models

Jacobo-Estrada

Santoyo-Sánchez

Thévenod

et al. 2017

IJMS

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Even decades after the discovery of Cadmium (Cd) toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters), the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization), in placenta and in fetus (teratogenicity, central nervous system, liver and kidney).

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“…These two concepts were united in a previous report showed that serum from PE women contain autoantibodies that bind and activate angiotensin II type 1 receptor (AT1R) 10 . Increasing studies from us and others [7][8][9][10][11][12][13] have shown that PE is a pregnancy-induced autoimmune disease in which key features of the disease result from the autoantibody, termed angiotensin II type 1 receptor autoantibody (AT1-AA). However, previous works have been restricted to confirmation of its pathophysiological relevance to PE and have been unable to specifically clarify the mechanisms for determining AT1-AA production.…”

Section: Introductionmentioning

confidence: 99%

Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1

Liu

Cheng

et al. 2020

Cell Death Dis

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Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality. Numerous studies have shown that women with PE develop autoantibody, termed angiotensin II type 1 receptor autoantibody (AT1-AA), and key features of the disease result from it. Emerging evidence has indicated that inflammatory cell necrosis, such as pyroptosis, could lead to autoantigen exposure and stimulate autoantibody production. Caspase-1, the central enzyme of inflammasome and key target of pyroptosis, may play roles in AT1R exposure and AT1-AA production. Exploring endogenous regulator that could inhibit AT1-AA production by targeting pyroptosis will be essential for treating PE. Lipoxin A 4 (LXA 4), endogenous dual anti-inflammatory and proresolving lipid mediator, may inhibit AT1-AA production via modulating caspase-1. Thus, we explore whether caspase-1 is essential for AT1-AA production and LXA 4 inhibits AT1-AA via modulating caspase-1. PE patients and mice developed AT1-AA associated with caspase-1 activation. Caspase-1 deletion leaded to AT1-AA decrease in PE mice. Consistent with these findings, we confirmed caspase-1 activation, trophoblast pyroptosis and AT1R exposure in PE mice and trophoblast model, while caspase-1 deficiency showed decreased trophoblast pyroptosis and AT1R exposure in vitro and in vivo. Interestingly, LXA 4 could suppress AT1-AA production via regulating caspase-1 as well as enhancing phagocytosis of dead trophoblasts by macrophages. These results suggest that caspase-1 promotes AT1-AA production via inducing trophoblast pyroptosis and AT1R exposure, while LXA 4 suppresses AT1-AA production via modulating caspase-1, supporting caspase-1 serving as a therapeutic target for attenuating AT1-AA and LXA 4 protecting patients from AT1-AA and PE.

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Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia

Cited by 45 publications

References 44 publications

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models

Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1

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