MicroRNA as novel mechanism in cyclosporine induced kidney fibrosis

Calcineurin inhibitors (CNIs) including cyclosporine A (CsA) and tacrolimus (FK506) have been revolutionary immunosuppressants for the prevention of allograft rejection in solid organ transplantation. While CNIs remain a mainstay of immunosuppressive therapy in organ transplantation, CNI-induced nephrotoxicity affects virtually every patient. Fibrosis is one of the major pathophysiological outcomes of CNI nephrotoxicity and remains a clinical challenge because the underlying mechanisms are incompletely understood and there are no therapeutic options to prevent or reverse renal damage. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression through modulation of mRNA stability and repression of target mRNA translation. There is increasing evidence that miRs are critical mediators of fibrosis and may be regulated by CNIs. In this study, 12 mice were randomly divided into two groups. 6 mice received CsA treatment for 4 weeks, the other 6 mice received placebo for 4 weeks. The miR expression profiles in the kidney tissues between mice that received CsA and placebo were compared by miR microarray. The miR microarray results strongly indicate that CsA induces significant changes in kidney miR expression profile. Using a combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50), 77 significantly regulated miRs were identified. 27 of the 77 selected miRs regulate genes in the TGFβ pathway, including miRs that have been reported to be involved in kidney fibrosis (such as miR21) and miRs that have not been reported to be related to kidney disease (such as miR28). Histology study of the kidney tissues from the CsA-treated mice showed clear signs of fibrosis. The mRNA expression profiles in the same kidney tissues between mice that received CsA and placebo were also compared with mRNA microarray. The mRNA and miR array data were analyzed in parallel. The results are consistent with regulation of the TGFβ pathway by miRs. In conclusion, CsA treatment can change the expression pattern of both miRs and mRNA in mouse a model. MiRs that regulate mRNAs in TGFβ pathway may play an important role in kidney fibrosis induced by CsA