Analyses of the toxic properties of recombinant human Cyclophilin A in mice

Kalinina, Anastasiia; Zamkova, Maria A.; Antoshina, Elena; Trukhanova, Lubov; Gorkova, Tatyana; Kazansky, Dmitry; Хромых, Л. М.

doi:10.1080/1547691x.2019.1665597

Cited by 11 publications

(5 citation statements)

References 38 publications

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“…High levels of CypA, similar to other pro-inflammatory cytokines, could impair placentation, leading to defects in fetal development and fetal death. This effect of CypA could be mediated by inducing the expression of serum amyloid alpha (SAA) [36]. SAA at significantly elevated concentrations inhibits trophoblast invasiveness [37] and contributes to early pregnancy loss [38].…”

Section: Discussionmentioning

confidence: 99%

“…Recombinant human cyclophilin A (rhCypA), schemes of administration. RhCypA (E. coli) was produced as previously described [36,70]. F1(CBA/Lac × C57BL/6) female and male mice (18-22 g) were mated, and females were selected the next morning by a copulative plug (0.5 day post-coitus, dpc).…”

Section: Discussionmentioning

confidence: 99%

“…These females were randomly divided into 3 groups and subcutaneously (s.c.) injected with 2.0 mg/mouse rhCypA in 200.0 µL PBS as follows: (1) 0.5-5.5 dpc (pre-implantation period) (n = 7); (2) 6.5-11.5 dpc (organogenesis) (n = 9); or (3) 12.5-17.5 dpc (fetogenesis) (n = 8). This rhCypA dose was chosen as the maximally tolerated dose without toxic effects under the course administration according to our preliminary studies [36]. Control females (n = 7) similarly received PBS for the whole gestation.…”

Section: Discussionmentioning

confidence: 99%

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Cyclophilin A as a Pro-Inflammatory Factor Exhibits Embryotoxic and Teratogenic Effects during Fetal Organogenesis

Kalinina

Semenova

Bruter

et al. 2023

IJMS

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The precise balance of Th1, Th2, and Th17 cytokines is a key factor in successful pregnancy and normal embryonic development. However, to date, not all humoral factors that regulate and influence physiological pregnancy have been completely studied. Our data here pointed out cyclophilin A (CypA) as the adverse pro-inflammatory factor negatively affecting fetal development and associated with pregnancy complications. In different mouse models in vivo, we demonstrated dramatic embryotoxicity and teratogenicity of increased CypA levels during pregnancy. Using generated transgenic models, we showed that CypA overexpression in fetal tissues induced the death of all transgenic fetuses and complete miscarriage. Administration of recombinant human CypA in a high dose to pregnant females during fetal organogenesis (6.5–11.5 dpc) exhibited teratogenic effects, causing severe defects in the brain and bone development that could lead to malformations and postnatal behavioral and cognitive disorders in the offspring. Embryotoxic and teratogenic effects could be mediated by CypA-induced up-regulation of M1 macrophage polarization via activation of the STAT1/3 signaling pathways. Here, we propose secreted CypA as a novel marker of complicated pregnancy and a therapeutic target for the correction of pregnancy complications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclophilin A as a Pro-Inflammatory Factor Exhibits Embryotoxic and Teratogenic Effects during Fetal Organogenesis

Kalinina

Semenova

Bruter

et al. 2023

IJMS

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“…Due to the great range of eCyps levels reported in patients (among 7.8 pg/ml and 3 μg/ml) ( Mutlu et al, 2017 ; Zhang et al, 2017 ; Alfonso et al, 2019 ), eCyps concentrations (0.25 and 0.5 μg/ml) were chosen based on previous works with endothelial cells and eCypA ( Kim et al, 2004 ; Jin et al, 2004 ; Xue et al, 2017 ), taking into account that the selected doses had pathophysiological relevance. Moreover, Cyps are highly conserved proteins, human and mouse sequences have near-full homology, so effects of human Cyps on in vitro and in vivo rodent models provide valuable outcomes ( Wang and Heitman, 2005 ; Kalinina et al, 2019 ; Cao et al, 2020 ). In this context, human recombinant proteins were used in order to mimic the pathological conditions observed in inflammation-based illnesses such as diabetes, cardiovascular and metabolic diseases.…”

Section: Methodsmentioning

confidence: 99%

Extracellular cyclophilins A and C induce dysfunction of pancreatic microendothelial cells

et al. 2022

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Extracellular cyclophilins (eCyps) A and B are chemotactic mediators in several illnesses in which inflammation plays an important role such as diabetes and cardiovascular diseases. Recently, eCypC has been reported as a potential biomarker for coronary artery disease but its effect in endothelium has not been determined. Moreover, there is a lack of studies with all these proteins in the same model, which makes difficult a direct comparison of their effects. In this work, MS1 pancreatic microendothelial cells were treated with eCyps A, B and C and their impact on endothelial function was analysed. eCyps A and C stimulated the release of IL-6 and MCP-1 and increased the expression of the receptor CD147, but eCypB did not affect these pro-inflammatory markers. Moreover, eCypC activated the translocation of NFkB-p65 to the nucleus. All these effects were reversed by pre-treatment with cyclosporine A. eCyps also produced endothelial dysfunction, as evidenced by the decrease in eNOS activation. Finally, the crosstalk among eCyps addition and their protein and gene expression was evaluated. eCypA generated a depletion in its protein and gene levels, whilst eCyps B and C upregulated their own protein expression. Moreover, each eCyp altered the intracellular expression of other Cyps, including cyclophilin D. This work is the first report of eCyps influence on iCyps expression, as well as the first description of eCypC as an activator of CD147 receptor and a mediator of endothelial dysfunction, which points to a potential role of this protein in vascular complications associated to diabetes.

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“…Indeed, CypA gene-deficient mice are protected from acetaminophen-induced liver toxicity and inflammation, leading to the description of CypA as a Damage-Associated Molecular Pattern [7]. Indeed, the administration of supraphysiologic doses of recombinant CypA to mice can induce systemic inflammation [8]. CD147, the only known CypA receptor, is also expressed by many non-leukocyte populations, including tubular epithelial cells of the kidney [1,9,10].…”

Section: Introductionmentioning

confidence: 99%

Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis

Leong

Ozols

Kanellis

et al. 2020

IJMS

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Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24 h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA−/− mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA−/− tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA−/− mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis.

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Analyses of the toxic properties of recombinant human Cyclophilin A in mice

Cited by 11 publications

References 38 publications

Cyclophilin A as a Pro-Inflammatory Factor Exhibits Embryotoxic and Teratogenic Effects during Fetal Organogenesis

Cyclophilin A as a Pro-Inflammatory Factor Exhibits Embryotoxic and Teratogenic Effects during Fetal Organogenesis

Extracellular cyclophilins A and C induce dysfunction of pancreatic microendothelial cells

Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis

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