Abstract
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 this study, we compared the renal microRNA expression profiles between mice that received CsA (20 mg/kg) or vehicle daily for six weeks. The results demonstrate that CsA induces significant changes in renal microRNA expression profile. We used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) and identified 76 differencially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis that includes 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.
Highlights
Cyclosporine A (CsA) and the related compound tacrolimus (Tac) are the cornerstones of immunosuppressant regimens in organ transplantations and autoimmune diseases
Kidney histology confirmed that CsA treatment induced cellular infiltration in the peri-arterial region that coincides with an increased collagen expression that extends into the tubulointerstitial space (Fig 1A)
Yellow represented overexpression of microRNAs while blue represented suppressed expression of microRNAs. These results demonstrated that CsA treatment substantially modified the microRNA expression profile in the mice kidney tissue
Summary
Cyclosporine A (CsA) and the related compound tacrolimus (Tac) are the cornerstones of immunosuppressant regimens in organ transplantations and autoimmune diseases. Despite significant improvements in morbidity and mortality following their introduction [1, 2], transplant patients treated with CsA or Tac frequently suffer from a range of side effects including cardiovascular disease and nephrotoxicity [3]. Acute and chronic kidney dysfunction after transplantation is one of the most common and serious postoperative complications [4]. The incidence rate of acute kidney dysfunction in heart transplant recipients can be as high as 70%[3]; 5–15% will eventually need renal replacement therapy [5]. The immunosuppressive effect of CsA and Tac is based on the inhibition of calcineurin, a calcium-dependent phosphatase required for the production of cytokines following T-cell receptor activation[6].
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