Immunosuppressive calcineurin inhibitor cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells

Kirschner, Karin M.; Demirci, Hasan; Himmerkus, Nina; Bachmann, S.; Mutig, Kerim

doi:10.1016/j.jbc.2022.101589

Cited by 16 publications

(23 citation statements)

References 57 publications

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“…Taurodeoxycholic acid (TUDCA), a hydrophilic bile acid derivative, is a classic er stress inhibitor ( 7 ). Studies have shown that TUDCA’s use is no longer limited to hepatobiliary diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we hypothesized that ox-LDL might induce calcification of valvular osteogenesis through ER stress, that is, ox-LDL is involved in osteogenesis of valvular interstitial cells through the classic ER stress pathway PERK-ATF4-CHOP, while ER stress inhibitors attenuated this effect. To this end, we isolated and cultured rabbit primary valve interstitial cells, administered ox-LDL-treated cells, observed the expression of PERK, ATF4, CHOP, and BMP2 in the ER stress pathway, and treated them with ER stress inhibitors ( 7 ). To further elucidate the role of PERK pathway in rabbit valve interstitial cell osteogenic differentiation, we hope to provide new therapeutic targets and ideas for the treatment and prevention of aortic valve calcification.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of Endoplasmic Reticulum Stress Pathway in the Osteogenic Phenotypic Transformation of Aortic Valve Interstitial Cells

et al. 2022

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Background and PurposeCalcific Aortic Valve Disease (CAVD) is a crucial component of degenerative valvular disease in old age and with the increasing prevalence of the aging population. we hope that by modeling valvular osteogenesis and intervening with endoplasmic reticulum stress inhibitor TUDCA to observe the effect of endoplasmic reticulum stress on valve osteogenesisMethodsIn this study, rabbit heart valvular interstitial cells (VICs) were isolated and cultured. They treated with ox-LDL (Oxidized Low Density Lipoprotein) stimulation to establish a model of valvular osteogenic transformation. BMP2 (Bone Morphogenetic Protein 2), PERK (Protein kinase R-like endoplasmic reticulum kinase), CHOP (CCAAT/enhancer-binding protein homologous protein) and transcriptional regulatory factor ATF4 (Activating Transcription Factor 4 )were recorded after intervention with ER stress inhibitor TUDCA. The effects of er stress on valvular osteogenic transformation were analyzed.ResultAfter stimulation of VICs with ox-LDL, the expression levels of BMP2, PERK, CHOP, and ATF4 increased. However, TUDCA treatment can alleviate the increased expression levels of BMP2, PERK ATF4, and CHOP under ox-LDL stimulation to a certain extent.ConclusionThe endoplasmic reticulum stress signaling pathway is involved in ox-LDL-induced calcification of rabbit valve interstitial cells. Inhibition of endoplasmic reticulum stress using TUDCA can improve the progression of rabbit aortic valve calcification.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of Endoplasmic Reticulum Stress Pathway in the Osteogenic Phenotypic Transformation of Aortic Valve Interstitial Cells

et al. 2022

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“…As mentioned above, a recent study has demonstrated that PPIA gene knockout can prevent ischemia/reperfusion-induced AKI, but is not protective against UUO-induced renal fibrosis 64 . A more recent study using small interring RNA (siRNA) specific to PPIA gene has demonstrated the induction of UPR by PPIA -knockdown in renal cells similar to the effects of CsA treatment to suppress CyPA function 96 . Therefore, knockout/knockdown of the PPIA gene encoding CyPA is another interesting aspect for future research on the theranostic roles of CyPA in kidney diseases to explore.…”

Section: Future Perspectivesmentioning

confidence: 96%

“…Indeed, CyPA also serves as a key modulator of CsA action. A recent study has demonstrated that knockdown of gene encoding CyPA ( PPIA ) in renal cells increases the unfolded protein response (UPR) similar to the effects of CsA treatment, which suppresses the CyPA chaperone function, leading to ER stress, UPR and renal epithelial cell apoptosis 96 . Modifying CyPA and/or UPR may help to reduce nephrotoxicity associated with CsA in renal transplantation 96 .…”

Section: Roles Of Cypa In Kidney Diseasesmentioning

confidence: 99%

“…A recent study has demonstrated that knockdown of gene encoding CyPA ( PPIA ) in renal cells increases the unfolded protein response (UPR) similar to the effects of CsA treatment, which suppresses the CyPA chaperone function, leading to ER stress, UPR and renal epithelial cell apoptosis 96 . Modifying CyPA and/or UPR may help to reduce nephrotoxicity associated with CsA in renal transplantation 96 . Another study has reported that polymorphism (-11G/C) on PPIA promoter is related to the nephrotoxicity after renal transplantation by affecting the PPIA gene expression 97 .…”

Section: Roles Of Cypa In Kidney Diseasesmentioning

confidence: 99%

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Current update on theranostic roles of cyclophilin A in kidney diseases

Hadpech¹,

Thongboonkerd²

2022

Theranostics

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Cyclophilin A (CyPA) or peptidylprolyl isomerase A (PPIA), an immunophilin with peptidyl-prolyl cis/trans isomerase (PPIase) activity, is an abundant cellular protein widely expressed across various cell types and tissues, including the kidney. Expression of CyPA in the kidney is relatively higher in proximal tubular epithelial cells than others along the nephron. Alterations in expression and secretion of CyPA play important roles in physiological processes and pathophysiology of several diseases affecting the kidney. Herein, we provide a brief overview of CyPA structural biology and present the current update on its theranostic roles in various kidney diseases, including diabetic nephropathy, acute kidney injury, chronic kidney disease, renal fibrosis, and nephrotoxicity associated with organ transplantation. Notably, the diagnostic/prognostic role for urinary CyPA in several of these kidney diseases is promising. Finally, future perspectives on the CyPA research, especially targeting CyPA for therapeutics, are discussed. A comprehensive understanding of the theranostic roles of CyPA in kidney diseases is expected to provide novel insights into the design of new therapeutic interventions and prevention strategies.

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Enhanced IGF‐IIRα Expression Exacerbates Lipopolysaccharide‐Induced Cardiac Inflammation, Hypertrophy, and Apoptosis Through Calcineurin Activation

Boonha,

Kuo,

Tsai

et al. 2024

Environmental Toxicology

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Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin‐like growth factor‐II receptor α (IGF‐IIRα) acts as a stress‐inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF‐IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)‐induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF‐IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF‐IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy‐related and inflammation‐related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF‐IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS‐treated H9c2 cardiac myoblasts with IGF‐IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis‐related cardiac mechanisms. Our study suggests that under sepsis‐like conditions in the heart with IGF‐IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF‐IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function.

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Immunosuppressive calcineurin inhibitor cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells

Cited by 16 publications

References 57 publications

Mechanism of Endoplasmic Reticulum Stress Pathway in the Osteogenic Phenotypic Transformation of Aortic Valve Interstitial Cells

Mechanism of Endoplasmic Reticulum Stress Pathway in the Osteogenic Phenotypic Transformation of Aortic Valve Interstitial Cells

Current update on theranostic roles of cyclophilin A in kidney diseases

Enhanced IGF‐IIRα Expression Exacerbates Lipopolysaccharide‐Induced Cardiac Inflammation, Hypertrophy, and Apoptosis Through Calcineurin Activation

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