Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

O’Connell, Séin; Slattery, Craig; Ryan, Michael P.; McMorrow, Tara

doi:10.1155/2012/980910

Cited by 10 publications

(8 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One in vitro study showed that rapamycin and cyclosporine A synergistically upregulated human mesangial cells' (HMCs) CCN2 expression and may also exert profibrotic effects. 35 Another in vitro study showed that rapamycin promoted CCN2 mRNA and protein expression in rat mesangial cells (RMCs) in transcriptional way. 36 An in vivo study 37 used a rat model of chronic nephrotoxicity to show that rapamycin further augmented CCN2 expression in kidney tissue and promoted kidney fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

Excessive production of connective tissue growth factor (CTGF, CCN2) and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, molecules and signal pathways regulating CCN2 expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin (mTOR) complex (mTORC), affects CCN2 expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with primary spontaneous pneumothorax and three with IPF. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor (TGF)-β1, or both. CCN2 and tissue inhibitor of metalloproteinase (TIMP)-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-β type I receptor (TβRI)/Smad inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-β1-induced CCN2 mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing CCN2 expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Findings that used other cell models are consistent with our results. One in vitro study 31 showed that rapamycin and cyclosporine A synergistically upregulated human mesangial cells' CTGF expression and may also exert profibrotic effects. Another in vitro study showed that rapamycin activated CTGF promoter and promoted CTGF mRNA and protein expression in rat mesangial cells (RMCs).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin regulates connective tissue growth factor expression of lung epithelial cells via phosphoinositide 3-kinase

Wan

Geng

et al. 2013

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains largely unknown. It is believed that IPF is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances (such as connective tissue growth factor, CTGF) that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and CTGF expression. Transformed epithelial cell line A549 and normal human pulmonary alveolar or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine CTGF mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting CTGF protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor (TGF)-β type I receptor (TβRI) inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-β1 induced CTGF expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on CTGF expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis.

show abstract

“…O’Connell and colleagues28 noted that cyclosporine used in concert with sirolimus had the effect of enhancing neural toxicity. Cyclosporine has also been shown to promote neoplasm and may cause neurotoxicity, hypertension, hyperlipidemia, and nephrotoxicity 29,30.…”

Section: Preclinical Studies and Adverse Effectsmentioning

confidence: 99%

Safety and Efficacy of Cyclosporine in the Treatment of Chronic Dry Eye

Schultz

2014

Ophthalmol Eye Dis

View full text Add to dashboard Cite

Dry-eye syndrome (DES) is a multifactorial disease affecting millions of individuals worldwide. Various factors, including age, hormonal status, genetics, sex, immune status, innervation status, nutrition, pathogens, and environmental stress, can alter the cellular and molecular structure or function of components of the ocular surface system. The resulting imbalance increases susceptibility to desiccation and epithelial damage, leading to a vicious circle in which inflammation amplifies and sustains further damage by chronic deregulation of the system. Lubricating agents and steroids have been used as treatment options. However, as the causes of the disease become better elucidated, the more chemically complex cyclosporine A has become an increasingly useful treatment option and in the United States is currently the only Food and Drug Administration (FDA)-approved prescription drug for the treatment of dry eye. The safety and efficacy of cyclosporine have been shown in numerous studies.

show abstract

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

Cited by 10 publications

References 39 publications

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Rapamycin regulates connective tissue growth factor expression of lung epithelial cells via phosphoinositide 3-kinase

Safety and Efficacy of Cyclosporine in the Treatment of Chronic Dry Eye

Contact Info

Product

Resources

About