Mechanisms of the calcium-dependent enzyme calcineurin and its isoform specificity in the development of kidney fibrosis
Location
Suwanee, GA
Start Date
14-5-2019 1:00 PM
End Date
14-5-2019 4:00 PM
Description
Calcineurin inhibitors, such as cyclosporine A (CsA), are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune side effects of the calcineurin inhibitors have significantly hindered their use. One major side effect is nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage. In this study, we attempt to unravel the mechanism of kidney fibrosis induced by calcineurin inhibitors using both high-throughput and traditional molecular biology approaches. We compared the renal microRNA and mRNA expression profiles between CsA-treated mice and controls. The results demonstrated that CsA induced significant changes in renal microRNA and mRNA expression profiles. This approach identified microRNAs and genes previously linked to renal fibrosis as well as those that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the TGF-β, Wnt and mTOR pathways. One of the genes regulated by the pathways is matrix metalloproteinase-9 (MMP9), which plays a key role during fibrosis. Calcineurin has two isoforms, CnAα and CnAβ. Both isoforms are ubiquitously expressed in the kidney. Using molecular biology approach, our data indicated that CsA-induced MMP9 secretion in kidney fibroblast was CnA isoform-specific. Furthermore, we investigated the cross talking between renal fibroblast and epithelial cells under CsA treatment. Our study showed that MMP9 was an important mediator of the cross-talking between renal epithelial and fibroblast cells during calcineurin inhibitor-induced kidney fibrosis, and the effect was also CnA isoform-specific. To further study the cross-talking between kidney fibroblast and epithelium cells in the development of kidney fibrosis, the change of all secreted proteins and peptides by the two cell types after CsA treatment are currently being screened by proteomics.
Embargo Period
1-28-2020
Mechanisms of the calcium-dependent enzyme calcineurin and its isoform specificity in the development of kidney fibrosis
Suwanee, GA
Calcineurin inhibitors, such as cyclosporine A (CsA), are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune side effects of the calcineurin inhibitors have significantly hindered their use. One major side effect is nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage. In this study, we attempt to unravel the mechanism of kidney fibrosis induced by calcineurin inhibitors using both high-throughput and traditional molecular biology approaches. We compared the renal microRNA and mRNA expression profiles between CsA-treated mice and controls. The results demonstrated that CsA induced significant changes in renal microRNA and mRNA expression profiles. This approach identified microRNAs and genes previously linked to renal fibrosis as well as those that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the TGF-β, Wnt and mTOR pathways. One of the genes regulated by the pathways is matrix metalloproteinase-9 (MMP9), which plays a key role during fibrosis. Calcineurin has two isoforms, CnAα and CnAβ. Both isoforms are ubiquitously expressed in the kidney. Using molecular biology approach, our data indicated that CsA-induced MMP9 secretion in kidney fibroblast was CnA isoform-specific. Furthermore, we investigated the cross talking between renal fibroblast and epithelial cells under CsA treatment. Our study showed that MMP9 was an important mediator of the cross-talking between renal epithelial and fibroblast cells during calcineurin inhibitor-induced kidney fibrosis, and the effect was also CnA isoform-specific. To further study the cross-talking between kidney fibroblast and epithelium cells in the development of kidney fibrosis, the change of all secreted proteins and peptides by the two cell types after CsA treatment are currently being screened by proteomics.