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Published on: November 10, 2021
Altered expression of alpha 2 beta 1 integrin in kidney fibroblasts: a potential mechanism for CsA-induced
Fatemeh Zal1, Zohreh Mostafavi-Pour2, Afagh Moattari3
11)Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 2)Reproductive Biology group, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.zmostafavipour@yahoo.co.uk.
Background:
Nephrotoxicity is considered a significant cause of patient morbidity following chronic Cyclosporine A (CsA) treatment. The exact mechanism of CsA-induced nephrotoxicity remains to be fully clarified. Tubulointerstitial fibrosis is widely regarded as a major pathway of CsA toxicity; therefore, the role of integrins as regulators of collagen in the extra-cellular matrix can be deemed pivotal. The objective of the present study was to observe the expression levels of alpha2beta1 integrin following CsA treatment +/- antioxidants.
Methods:
Adhesion assay, immunofluorescent and flow cytometric analyses were performed on kidney fibroblasts obtained from rats after administration of CsA (25 mg/kg/day) +/- Vitamin E (vit. E) and Quercetin (Q) for 4 weeks. Total RNA was collected from the aforementioned fibroblasts for semi-quantitative reverse transcriptase-polymerase chain reaction analysis of α2 and β1 integrins.
Results:
We found that α2 and β1 integrins were both markedly reduced following treatment with CsA, i.e., 25% and 13%, respectively, but were normal following subsequent consumption of the antioxidants vit. E and Q. Attachment and spreading of the CsA-treated fibroblasts declined from 82% to 50%; however, this effect was partially reversed to 70% following antioxidant treatment. Similar results were observed in the spreading assay in which the level of spreading decreased from 73% to 21% and was subsequently restored to 46%.
Conclusion:
We conclude that cell adhesion, mediated by binding of integrin to collagen, which is a prerequisite of normal cell viability and collagen regulation, may be a novel pathway further explaining the nephrotoxic effects of CsA.
Insights
Cyclosporine A (CsA) reduces alpha2beta1 integrin expression, impairing kidney cell adhesion. Antioxidants Vitamin E and Quercetin restore integrin levels and cell function, suggesting a novel mechanism for CsA nephrotoxicity.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Chronic Cyclosporine A (CsA) treatment causes significant patient morbidity due to nephrotoxicity.
- The precise mechanisms underlying CsA-induced kidney damage are not fully understood.
- Tubulointerstitial fibrosis is a key pathway in CsA toxicity, highlighting the role of integrins in extracellular matrix collagen regulation.
Purpose of the Study:
- To investigate the expression levels of alpha2beta1 integrin in kidney cells following CsA administration.
- To evaluate the effect of antioxidants Vitamin E and Quercetin on CsA-induced changes in integrin expression and function.
Main Methods:
- Kidney fibroblasts were isolated from rats treated with CsA (25 mg/kg/day) with or without Vitamin E and Quercetin for 4 weeks.
- Adhesion, immunofluorescence, and flow cytometry assays were performed.
- Semi-quantitative reverse transcriptase-polymerase chain reaction analyzed alpha2 and beta1 integrin mRNA levels.
Main Results:
- CsA treatment significantly reduced alpha2 and beta1 integrin expression by 25% and 13%, respectively.
- Fibroblast attachment decreased from 82% to 50% and spreading from 73% to 21% after CsA exposure.
- Antioxidant treatment with Vitamin E and Quercetin normalized integrin expression and partially restored cell attachment (to 70%) and spreading (to 46%).
Conclusions:
- Integrin-mediated cell adhesion to collagen is crucial for cell viability and collagen regulation.
- Reduced integrin expression and function may represent a novel pathway contributing to Cyclosporine A nephrotoxicity.
- Antioxidants show potential in mitigating CsA-induced kidney damage by preserving integrin function.
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