Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts
- Department of Pharmaceutical Science, School of Pharmacy, Philadelphia College of Osteopathic Medicine, Suwanee, GA (United States)
Highlights: • Regulation of CsA-induced MMP-9 production and activity in renal fibroblasts is CnA isoform specific. • The CnAβ isoform is associated with enhanced secreted MMP-9 while the CnAα isoform is associated with significantly low levels of secreted MMP-9. • CsA-mediated induction of MMP-9 secretion in renal fibroblasts may be regulated by cross-talk between CnAβ isoform and the TGF-β/Smad3 pathway. • Intracellular MMP-9 expression in CnAβ{sup −/−} renal fibroblasts is enhanced by CsA. Long-term treatment with the potent immunosuppressive drug cyclosporine A (CsA) results in chronic nephrotoxicity. Its immunosuppressive properties are due to the inhibition of the calcium- and calmodulin-dependent phosphatase protein calcineurin A (CnA) which has three catalytic isoforms. Of those, the CnAα and β isoforms are ubiquitously expressed, particularly in the kidney. Additionally, chronic nephrotoxicity has been associated with an imbalance of extracellular matrix (ECM) synthesis and degradation resulting in an accumulation of ECM molecules. This study evaluates whether the expressions of matrix metalloproteinases (MMP-2 and MMP-9) induced by CsA are calcineurin isoform specific. Wild-type (WT), CnAα knockout (CnAα{sup −/−}) and CnAβ knockout (CnAβ{sup −/−}) kidney fibroblast cell lines (an in vitro innovative tool that was previously created in our lab) were treated with CsA at 10 ng/ml for 48 h. ELISA analysis demonstrated that the CsA-induced secretion profile of MMP-9 was highest in CnAα{sup −/−} cells and lowest in CnAβ{sup −/−} cells vs. WT cells. In contrast, CsA did not induce an increase in MMP-2 protein levels in WT, CnAα{sup −/−} nor CnAβ{sup −/−} renal fibroblasts. These results indicate that MMP-9 secretion is CnA-isoform specific, i.e. the CnAβ isoform contributes to the CsA-induced upregulation of MMP-9 while the CnAα does not. As such, understanding the role of calcineurin A isoforms in the regulation of the homeostasis of ECM degradation in the kidney after long-term CsA treatment needs to be further investigated.
- OSTI ID:
- 23134272
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 4; Other Information: Copyright (c) 2018 Published by Elsevier Inc.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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