Abstract
Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1 mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Tacrolimus also affected renal miRNA expression, including miRNAs previously involved in fibrotic and inflammatory processes as “fibromirs” such as miR-21-5p, miR-199a-5p and miR-214-3p. In agreement with in vivo data, Renal Proximal Tubular Epithelial cells exposed to Tacrolimus (25 and 50 µM) showed upregulation of miR-21-5p and the concomitant induction of epithelial phenotypic changes, inflammation and oxidative stress. In conclusion, this study suggests for the first time that miRNAs, especially fibromiRs, participate to Tacrolimus-induced nephrotoxic effects. Therefore, targeting miRNAs may be a new therapeutic option to counteract Tacrolimus deleterious effects on kidney.
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References
Baxter RM, Crowell TP, George JA et al (2007) The plant pathogenesis related protein GLIPR-2 is highly expressed in fibrotic kidney and promotes epithelial to mesenchymal transition in vitro. Matrix Biol J Int Soc Matrix Biol 26:20–29. https://doi.org/10.1016/j.matbio.2006.09.005
Brook NR, Waller JR, Bicknell GR, Nicholson ML (2005) The experimental agent pirfenidone reduces pro-fibrotic gene expression in a model of tacrolimus-induced nephrotoxicity. J Surg Res 125:137–143. https://doi.org/10.1016/j.jss.2004.12.007
Castro NE, Kato M, Park JT, Natarajan R (2014) Transforming growth factor b1 (TGF-b1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells. J Biol Chem 289:29001–29013. https://doi.org/10.1074/jbc.M114.600783
Chau BN, Xin C, Hartner J et al (2012) MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 4:121ra18-121ra18. https://doi.org/10.1126/scitranslmed.3003205
Chen J, Zmijewska A, Zhi D, Mannon RB (2015) Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling. Transpl Int 28:232–245. https://doi.org/10.1111/tri.12471
Chiasson VL, Jones KA, Kopriva SE et al (2012) Endothelial cell transforming growth factor-b receptor activation causes tacrolimus-induced renal arteriolar hyalinosis. Kidney Int 82:857–866. https://doi.org/10.1038/ki.2012.104
Chung AC-K, Lan HY (2015) MicroRNAs in renal fibrosis. Front Physiol. https://doi.org/10.3389/fphys.2015.00050
de Arriba G, Calvino M, Benito S, Parra T (2013) Cyclosporine A-induced apoptosis in renal tubular cells is related to oxidative damage and mitochondrial fission. Toxicol Lett 218:30–38. https://doi.org/10.1016/j.toxlet.2013.01.007
Denby L, Ramdas V, Lu R et al (2014) MicroRNA-214 antagonism protects against renal fibrosis. J Am Soc Nephrol 25:65–80. https://doi.org/10.1681/ASN.2013010072
Ding L, Karanam NK, Yordy JS, Giri U, Story MD (2015) miRNA associated with distal metastasis and local recurrence after postoperative radiotherapy in high-risk head and neck cancer 75(15) https://doi.org/10.1158/1538-7445.AM2015-3998 (Abstract 3998)
El-Zoghby ZM, Stegall MD, Lager DJ et al (2009) Identifying specific causes of kidney allograft loss. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 9:527–535. https://doi.org/10.1111/j.1600-6143.2008.02519.x
Ferjani H, Achour A, Bacha H, Abid S (2015) Tacrolimus and mycophenolate mofetil associations: Induction of oxidative stress or antioxidant effect? Hum Exp Toxicol 34:1119–1132. https://doi.org/10.1177/0960327115569812
Friedman RC, Farh KK-H, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105. https://doi.org/10.1101/gr.082701.108
Galichon P, Bataille A, Vandermeersch S et al (2017) Stress response gene Nupr1 alleviates cyclosporin a nephrotoxicity in vivo. J Am Soc Nephrol 28:545–556. https://doi.org/10.1681/ASN.2015080936
Galletti P, Di Gennaro CI, Migliardi V et al (2005) Diverse effects of natural antioxidants on cyclosporin cytotoxicity in rat renal tubular cells. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc 20:1551–1558. https://doi.org/10.1093/ndt/gfh846
Glowacki F, Savary G, Gnemmi V et al (2013) Increased circulating miR-21 levels are associated with kidney fibrosis. PLoS One 8:e58014. https://doi.org/10.1371/journal.pone.0058014
Godwin JG, Ge X, Stephan K et al (2010) Identification of a microRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci USA 107:14339–14344. https://doi.org/10.1073/pnas.0912701107
Gomez IG, Nakagawa N, Duffield JS (2016) MicroRNAs as novel therapeutic targets to treat kidney injury and fibrosis. Am J Physiol Renal Physiol 310:F931-944. https://doi.org/10.1152/ajprenal.00523.2015
Gooch JL, King C, Francis CE et al (2017) Cyclosporine A alters expression of renal microRNAs: new insights into calcineurin inhibitor nephrotoxicity. PloS One 12:e0175242. https://doi.org/10.1371/journal.pone.0175242
Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu Rev Med 57:365–380. https://doi.org/10.1146/annurev.med.57.121304.131342
Hennino M-F, Buob D, Van der Hauwaert C et al (2016) miR-21-5p renal expression is associated with fibrosis and renal survival in patients with IgA nephropathy. Sci Rep 6:27209. https://doi.org/10.1038/srep27209
Hyun J, Park J, Wang S et al (2016) MicroRNA expression profiling in CCl4-induced liver fibrosis of mus musculus. Int J Mol Sci. https://doi.org/10.3390/ijms17060961
Jiang T, Acosta D (1993) An in vitro model of cyclosporine-induced nephrotoxicity. Fundam Appl Toxicol Off J Soc Toxicol 20:486–495
Justo P, Lorz C, Sanz A et al (2003) Intracellular mechanisms of cyclosporin A-induced tubular cell apoptosis. J Am Soc Nephrol 14:3072–3080
Kidokoro K, Satoh M, Nagasu H et al (2012) Tacrolimus induces glomerular injury via endothelial dysfunction caused by reactive oxygen species and inflammatory change. Kidney Blood Press Res 35:549–557. https://doi.org/10.1159/000339494
Leelahavanichkul A, Yan Q, Hu X et al (2010) Angiotensin II overcomes strain-dependent resistance of rapid CKD progression in a new remnant kidney mouse model. Kidney Int 78:1136–1153. https://doi.org/10.1038/ki.2010.287
Liu X-J, Hong Q, Wang Z et al (2015) MicroRNA21 promotes interstitial fibrosis via targeting DDAH1: a potential role in renal fibrosis. Mol Cell Biochem 411:181–189. https://doi.org/10.1007/s11010-015-2580-2
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2–∆∆CT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Luo L, Sun Z, Wu W, Luo G (2012) Mycophenolate mofetil and FK506 have different effects on kidney allograft fibrosis in rats that underwent chronic allograft nephropathy. BMC Nephrol 13:53. https://doi.org/10.1186/1471-2369-13-53
Martin-Martin N, Ryan G, McMorrow T, Ryan MP (2010) Sirolimus and cyclosporine A alter barrier function in renal proximal tubular cells through stimulation of ERK1/2 signaling and claudin-1 expression. Am J Physiol Renal Physiol 298:F672-682. https://doi.org/10.1152/ajprenal.00199.2009
McClelland AD, Herman-Edelstein M, Komers R et al (2015) miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. Clin Sci Lond Engl 129:1237–1249. https://doi.org/10.1042/CS20150427
Meng X-M, Chung ACK, Lan HY (2013) Role of the TGF-b/BMP-7/Smad pathways in renal diseases. Clin Sci Lond Engl 124:243–254. https://doi.org/10.1042/CS20120252
Naesens M, Kuypers DRJ, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4:481–508. https://doi.org/10.2215/CJN.04800908
Nankivell BJ, Borrows RJ, Fung CL-S et al (2003) The natural history of chronic allograft nephropathy. N Engl J Med 349:2326–2333. https://doi.org/10.1056/NEJMoa020009
Pottier N, Cauffiez C, Perrais M et al (2014) FibromiRs: translating molecular discoveries into new anti-fibrotic drugs. Trends Pharmacol Sci 35:119–126. https://doi.org/10.1016/j.tips.2014.01.003
Pratschke S, Bilzer M, Grützner U et al (2012) Tacrolimus preconditioning of rat liver allografts impacts glutathione homeostasis and early reperfusion injury. J Surg Res 176:309–316. https://doi.org/10.1016/j.jss.2011.07.045
Rodrigues-Diez R, González-Guerrero C, Ocaña-Salceda C et al (2016) Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling. Sci Rep 6:27915. https://doi.org/10.1038/srep27915
Roy S, Benz F, Vargas Cardenas D et al (2015) miR-30c and miR-193 are a part of the TGF-b-dependent regulatory network controlling extracellular matrix genes in liver fibrosis. J Dig Dis 16:513–524. https://doi.org/10.1111/1751-2980.12266
Shihab FS, Bennett WM, Tanner AM, Andoh TF (1997) Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation 64:1829–1837
Snanoudj R, Royal V, Elie C et al (2011) Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy: histological signs of CNI toxicity. Am J Transplant 11:2635–2646. https://doi.org/10.1111/j.1600-6143.2011.03718.x
Torres IB, Moreso F, Sarró E et al (2014) The interplay between inflammation and fibrosis in kidney transplantation. BioMed Res Int 2014:750602. https://doi.org/10.1155/2014/750602
Van der Hauwaert C, Savary G, Buob D et al (2014) Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models. Toxicol Appl Pharmacol 279:409–418. https://doi.org/10.1016/j.taap.2014.07.007
Van der Hauwaert C, Savary G, Hennino M-F et al (2015) Implication des microARN dans la fibrose rénale. Néphrologie Thérapeutique 11:474–482
Xiong M, Jiang L, Zhou Y et al (2012) The miR-200 family regulates TGF-b1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression. Am J Physiol Renal Physiol 302:F369-379. https://doi.org/10.1152/ajprenal.00268.2011
Yuan J, Benway CJ, Bagley J, Iacomini J (2015) MicroRNA-494 promotes cyclosporine-induced nephrotoxicity and epithelial to mesenchymal transition by inhibiting PTEN: MicroRNAs and cyclosporine nephrotoxicity. Am J Transplant 15:1682–1691. https://doi.org/10.1111/ajt.13161
Acknowledgements
The authors gratefully thank M-H Gevaert (Laboratoire d’Histologie, Faculté de Médecine de Lille) and D Taillieu (Animalerie Haute Technologie, Faculté de Médecine de Lille) for their technical help. The authors gratefully also acknowledge the technical support of V. Magnone, N. Pons, G. Rios (UCA GenomiX platform of the University Cote d’Azur).
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This study was supported by Santelys association.
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Vandenbussche, C., Van der Hauwaert, C., Dewaeles, E. et al. Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation. Arch Toxicol 92, 1539–1550 (2018). https://doi.org/10.1007/s00204-018-2158-3
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DOI: https://doi.org/10.1007/s00204-018-2158-3