Transgenic mice overexpressing cyclophilin A are resistant to cyclosporin A-induced nephrotoxicity via peptidyl-prolyl cis–trans isomerase activity

Hong, Feng; Lee, Jinhwa; Piao, Yu Ji; Jae, Yeong Kwon; Kim, Young-Joo; Oh, Chang‐Kyu; Seo, Jeong-Sun; Yun, Yeon-Sook; Yang, Chul Woo; Ha, Joohun; Kim, Sung Soo

doi:10.1016/j.bbrc.2004.02.160

Cited by 37 publications

(24 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, CYP increases peroxiredoxin activity, and protects cardiac myoblasts against CSA-induced toxicity (27). Transgenic mice overexpressing CYP are resistant to CSA-induced nephrotoxicity (28). In this respect, a strategy aimed at blocking Cn activity directly without affecting CYP, such as CABIN-1 overexpression, is needed to minimize the side effects of CSA.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To determine whether intracellular calcineurin (Cn), a calcium-activated phosphatase, regulates the anabolic and catabolic activities of chondrocytes, and is a potential target in the treatment of osteoarthritis (OA).Methods. CnA expression was examined in cartilage tissue samples and cultured chondrocytes from OA patients, using immunohistochemistry and Western blot analysis, respectively. Concentrations of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the culture supernatants were determined using enzyme-linked immunosorbent assay. Levels of nitric oxide (NO) and type II collagen (CII) were measured using the Griess reaction and Western blot analysis, respectively. In addition, the pathologic role of Cn was examined in an in vivo model in which experimental OA was induced in mice by injecting type VII collagenase into the knee joints.Results. CnA was highly expressed in the chondrocytes of lesional OA cartilage. Cyclosporin A (CSA), a Cn inhibitor, inhibited spontaneous and interleukin-1␤-stimulated production of NO, MMP-1, and MMP-3 in chondrocytes. However, CSA increased the levels of production of CII, TIMP-1, and transforming growth factor ␤. Similar changes in MMP-1, NO, and CII expression levels in chondrocytes were observed after the targeted inhibition of Cn by overexpression of calcineurin binding protein 1, a natural Cn antagonist. Moreover, in the mouse model, animals treated with CSA showed a significant decrease in both the extent and the severity of cartilage damage, which were assessed macroscopically and microscopically, compared with vehicle-treated animals.Conclusion. These results suggest that CnA is critically involved in the catabolic and anabolic activities of chondrocytes as well as in the progression of experimental OA. Targeted inhibition of CnA may be an effective treatment strategy for OA.The failure of chondrocytes to maintain cartilage integrity is a key event leading to joint destruction in many arthritic conditions, including rheumatoid arthritis (RA), osteoarthritis (OA), and septic arthritis (1,2). Chondrocytes respond to a variety of stimuli, including proinflammatory cytokines and mechanical loading, by increasing the concentration of cartilage degradative enzymes and catabolic mediators. A disturbance in the regulation of the anabolic and catabolic activities of chondrocytes can result in a net loss of cartilage matrix components. Regardless of the initiating stimuli, the key process in cartilage degradation is similar, involving specific matrix metalloproteinases (MMPs), nitric oxide (NO), and aggrecanases, which are members of the ADAMTS family (3). Previous studies have demonstrated that interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) also play key roles in cartilage degradation by stimulating their own production and inducing chondrocytes to produce MMPs and NO (4,5).

show abstract

Section: Discussionmentioning

confidence: 99%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…Cyclosporin toxicity is presumed due to inhibition of cyclophillin-mediated PPIase activity and initiation of reactive oxidative stress. Cyclophillin functions as an antioxidant (27), as PPIase activity regulates intracellular trafficking (28), cell cycle (29), transcription (30) and differentiation (31). While the final pathway to IL-2 gene transcription may coincide, differences between the immunophilin families also exist.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

Neuringer

Sloan

Budd

et al. 2005

American Journal of Transplantation

View full text Add to dashboard Cite

Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-b stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (a and b ), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10 000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-b stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of welldifferentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.

show abstract

“…1). В результате отмены действия кальцийнейрина блокируется переход ядерного фактора активированных Т-лимфоцитов из цитоплазмы в ядро, что препятствует транскрипции генов, кодирующих различные цитокины, в частности интерлейкин 2 [6], дефицит которого подавляет раз-витие Т-клеточного иммунного ответа.…”

unclassified

“…Все циклофилины обла-дают пептидил-пролил-цис-транс-изомеразной актив-ностью (рис. 2), которая играет важную роль в фолдинге и сборке мультидоменных белков [6], внутриклеточном транспорте белков, поддержании стабильности мульти-белковых комплексов, регуляции транскрипции и кле-точного цикла, а также в передаче сигнала от Т-кле-точного рецептора и клеточной дифференцировке [7].…”

unclassified

“…Самый высокий уровень данного белка отмечает-ся в головном мозге, в частности в коре головного мозга и гиппокампе, при этом в нейронах, особенно в клет-ках Пуркинье, его содержится больше, чем в клетках глии [5,11]. [6]. Помимо общих для всех членов семейства функ-ций, внутриклеточный циклофилин А обладает анти-оксидантными свойствами.…”

unclassified

See 1 more Smart Citation

Cyclophilin A: Structure and Functions

Kalinina¹,

Хромых²,

Kazanskii³

2017

Usp. mol. onkol

View full text Add to dashboard Cite

Transgenic mice overexpressing cyclophilin A are resistant to cyclosporin A-induced nephrotoxicity via peptidyl-prolyl cis–trans isomerase activity

Cited by 37 publications

References 37 publications

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

Cyclophilin A: Structure and Functions

Contact Info

Product

Resources

About