Kidney injury by cyclosporine A is aggravated in heme oxygenase-1 deficient mice and involves regulation of microRNAs
Cyclosporine A (CsA), a widely used immunosuppressive drug, exerts nephrotoxic activities, as demonstrated by increased tubulointerstitial fibrosis, inflammation and podocyte damage. Recently, a number of microRNAs expressed in the kidney have been reported to be elevated during renal damage. Our aim was to investigate the effect of CsA on selected microRNAs in the mouse kidney after CsA treatment. Moreover, as heme oxygenase-1 (HO-1, encoded by the Hmox1 gene) was shown to play a protective role during kidney disorders, we assessed whether HO-1 deficiency in vivo influences the CsA-regulated microRNAs’ expression. We have observed that the pro-fibrotic miR-21 and pro-apoptotic miR-34a expression was upregulated in kidneys of HO-1 deficient mice and it was further enhanced by CsA. Concomitantly, the level of anti-fibrotic microRNAs, belonging to miR-29 and miR-200 families, was down-regulated after CsA treatment. Generally, Hmox1 knock-out (Hmox1–/–) animals were more susceptible to CsA treatment, as the mortality rate was 4 out of 9 Hmox1–/– mice, and increased fibrosis (Tgfb2, Pai1), inflammation (Il6) and apoptosis (Cdkn1a-p21) were noticed in the HO-1 deficient kidneys. In summary, our data demonstrate that CsA induces significant changes in the expression of renal microRNAs and emphasize HO-1 deficiency as an important factor contributing to the CsA-mediated renal toxicity.
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