Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation; however, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood. MicroRNAs are short non-coding RNAs that regulate protein-coding RNA expression through post-translational repression of target messenger RNAs. MicroRNA dysregulation is known to be involved in kidney diseases including fibrosis. In a recent study, a team led by researchers from Philadelphia College of Osteopathic Medicine compared the renal microRNA microarray expression profiles between mice that received CsA (20 mg/kg) or vehicle daily for six weeks. Their results demonstrate that CsA induces significant changes in renal microRNA expression profile.
Researchers used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) to identify 76 differentially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis, including let-7d, miR-21, miR-29, miR-30, miR-130, miR-192, and miR-200 as well as microRNAs that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the Wnt, TGF-β, mTOR, and VEGF pathways. The mRNA expression profiles were compared in the same samples. The change of mRNA and microRNA profiles showed close correlations. To validate that the observed microRNA and mRNA expression level changes in mice kidney tissue were directly related to CsA treatment, the expression change induced by CsA treatment of three microRNAs (miR-21, miR-186, and miR-709) and three mRNAs (BMPR1a, SMURF1 and SMAD7) were compared in HEK293 cell line. A similar trend of expression level change was induced by CsA treatment in all selected microRNAs and mRNAs in the in vitro cell model.
These data provide a roadmap for future work to study the role of the known and novel candidate microRNAs in the mechanism of nephrotoxicity and their further therapeutic potential.
J. L. Gooch, C. King, C. E. Francis, P. S. Garcia, Y. Bai (2017) Cyclosporine A alters expression of renal microRNAs: New insights into calcineurin inhibitor nephrotoxicity PLoS ONE 12(4): e0175242. doi: 10.1371/journal.pone.0175242 [article]