Abstract
During peritoneal dialysis (PD), peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype that, together with the inflammatory process, promotes tissue fibrosis and a failure of peritoneal membrane function. To date, there is no definitive treatment for the progressive thickening and angiogenesis of the peritoneal membrane associated with PD. In this study we tested, in vitro and in vivo, the ability of active compounds extracted from extra virgin olive oil (AC-EVOO) to counteract the mesothelial-to-mesenchymal transition process (MMT) observed in mesothelial cells chronically exposed to the conventional peritoneal dialysate (DL). In particular, we used a cultivar from southern Italy known to have a high polyphenol content. Our results showed that, in mesothelial cells exposed to DL, the combined treatment with AC-EVOO prevented the genic and protein upregulation of key mesenchymal and inflammatory markers, as well as the MCs’ migratory capacity. Concomitantly, we tested the antifibrotic efficacy of AC-EVOO in mesothelial cells obtained from effluents of patients undergoing PD, whose “fibroblast-like” phenotype was defined by flow-cytometry assay. We observed that in these cells AC-EVOO significantly mitigated, but did not reverse, the MMT process. In conclusion, our preliminary results suggest that AC-EVOO can interfere with critical factors in the process of differentiation, preventing myofibroblast formation, but once fibrosis has already progressed it is unable to promote the redifferentiation to the epithelial phenotype. Further studies are needed to establish whether AC-EVOO could represent a new therapeutic target to prevent peritoneal fibrosis.
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De Nicola L, Donfrancesco C, Minutolo R, Lo Noce C, De Curtis A, Palmieri L, Iacoviello L, Conte G, Chiodini P, Sorrentino F, Coppo R, Vanuzzo D, Scherillo M, Giampaoli S (2011) Epidemiology of chronic kidney disease in Italy: current state and contribution of the CARHES study. Giornale italiano di nefrologia 28(4):401–407
De Nicola L, Donfrancesco C, Minutolo R, Lo Noce C, Palmieri L, De Curtis A, Iacoviello L, Zoccali C, Gesualdo L, Conte G, Vanuzzo D, Giampaoli S (2015) Prevalence and cardiovascular risk profile of chronic kidney disease in Italy: results of the 2008-12 National Health Examination Survey. Nephrol Dial Transplant 30(5):806–814. doi:10.1093/ndt/gfu383
Chaudhary K, Sangha H, Khanna R (2011) Peritoneal dialysis first: rationale. Clin J Am Soc Nephrol 6(2):447–456. doi:10.2215/cjn.07920910
Loureiro J, Aguilera A, Selgas R, Sandoval P, Albar-Vizcaino P, Perez-Lozano ML, Ruiz-Carpio V, Majano PL, Lamas S, Rodriguez-Pascual F, Borras-Cuesta F, Dotor J, Lopez-Cabrera M (2011) Blocking TGF-beta1 protects the peritoneal membrane from dialysate-induced damage. J Am Soc Nephrol 22(9):1682–1695. doi:10.1681/asn.2010111197
Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, Dominguez-Jimenez C, Jimenez-Heffernan JA, Aguilera A, Sanchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sanchez-Madrid F, Lopez-Cabrera M (2003) Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 348(5):403–413. doi:10.1056/NEJMoa020809
Ditsawanon P, Aramwit P (2015) Preserving the peritoneal membrane in long-term peritoneal dialysis patients. J Clin Pharm Ther. doi:10.1111/jcpt.12318
Aroeira LS, Aguilera A, Sanchez-Tomero JA, Bajo MA, del Peso G, Jimenez-Heffernan JA, Selgas R, Lopez-Cabrera M (2007) Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions. J Am Soc Nephrol 18(7):2004–2013. doi:10.1681/asn.2006111292
Bulotta S, Celano M, Lepore SM, Montalcini T, Pujia A, Russo D (2014) Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases. J Transl Med 12:219. doi:10.1186/s12967-014-0219-9
Vazquez-Martin A, Fernandez-Arroyo S, Cufi S, Oliveras-Ferraros C, Lozano-Sanchez J, Vellon L, Micol V, Joven J, Segura-Carretero A, Menendez JA (2012) Phenolic secoiridoids in extra virgin olive oil impede fibrogenic and oncogenic epithelial-to-mesenchymal transition: extra virgin olive oil as a source of novel antiaging phytochemicals. Rejuvenation Res 15(1):3–21. doi:10.1089/rej.2011.1203
Olive Council (2013) Determination of biophenols in olive oil by HPLC. COIT.20Doc No 29 November 2009. http://www.internationaloliveoil.org/documents/viewfile/4141-met29eng. Accessed 26 Sept 2016
Vizza D, Perri A, Lofaro D, Toteda G, Lupinacci S, Leone F, Gigliotti P, Papalia T, Bonofiglio R (2013) Exposure to nerve growth factor worsens nephrotoxic effect induced by Cyclosporine A in HK-2 cells. PLoS One 8(11):e80113. doi:10.1371/journal.pone.0080113
De Amicis F, Perri A, Vizza D, Russo A, Panno ML, Bonofiglio D, Giordano C, Mauro L, Aquila S, Tramontano D, Ando S (2013) Epigallocatechin gallate inhibits growth and epithelial-to-mesenchymal transition in human thyroid carcinoma cell lines. J Cell Physiol 228(10):2054–2062. doi:10.1002/jcp.24372
Tomei P, Masola V, Granata S, Bellin G, Carratu P, Ficial M, Ventura VA, Onisto M, Resta O, Gambaro G, Chilosi M, Lupo A, Zaza G (2016) Everolimus-induced epithelial to mesenchymal transition (EMT) in bronchial/pulmonary cells: when the dosage does matter in transplantation. J Nephrol 29(6):881–891. doi:10.1007/s40620-016-0295-4
Hinz B, Gabbiani G (2010) Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives. F1000 Biol Rep 2:78. doi:10.3410/b2-78
Krediet RT (1999) The peritoneal membrane in chronic peritoneal dialysis. Kidney Int 55(1):341–356. doi:10.1046/j.1523-1755.1999.00264.x
Krediet RT, Lindholm B, Rippe B (2000) Pathophysiology of peritoneal membrane failure. Perit Dial Int 20(Suppl 4):S22–S42
Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, Mackenzie RK, Williams GT (2002) Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 13(2):470–479
Witowski J, Kawka E, Rudolf A, Jorres A (2015) New developments in peritoneal fibroblast biology: implications for inflammation and fibrosis in peritoneal dialysis. BioMed Res Int 2015:134708. doi:10.1155/2015/134708
Shin HS, Ryu ES, Oh ES, Kang DH (2015) Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells. Lab Invest 95(10):1157–1173. doi:10.1038/labinvest.2015.91
Del Peso G, Jimenez-Heffernan JA, Bajo MA, Aroeira LS, Aguilera A, Fernandez-Perpen A, Cirugeda A, Castro MJ, de Gracia R, Sanchez-Villanueva R, Sanchez-Tomero JA, Lopez-Cabrera M, Selgas R (2008) Epithelial-to-mesenchymal transition of mesothelial cells is an early event during peritoneal dialysis and is associated with high peritoneal transport. Kidney Int Suppl 108:S26–S33. doi:10.1038/sj.ki.5002598
Yu MA, Shin KS, Kim JH, Kim YI, Chung SS, Park SH, Kim YL, Kang DH (2009) HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium. J Am Soc Nephrol 20(3):567–581. doi:10.1681/asn.2008040424
Guo H, Leung JC, Lam MF, Chan LY, Tsang AW, Lan HY, Lai KN (2007) Smad7 transgene attenuates peritoneal fibrosis in uremic rats treated with peritoneal dialysis. J Am Soc Nephrol 18(10):2689–2703. doi:10.1681/asn.2007010121
Loureiro J, Schilte M, Aguilera A, Albar-Vizcaino P, Ramirez-Huesca M, Perez-Lozano ML, Gonzalez-Mateo G, Aroeira LS, Selgas R, Mendoza L, Ortiz A, Ruiz-Ortega M, van den Born J, Beelen RH, Lopez-Cabrera M (2010) BMP-7 blocks mesenchymal conversion of mesothelial cells and prevents peritoneal damage induced by dialysis fluid exposure. Nephrol Dial Transplant 25(4):1098–1108. doi:10.1093/ndt/gfp618
Casaburi I, Puoci F, Chimento A, Sirianni R, Ruggiero C, Avena P, Pezzi V (2013) Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies. Mol Nutr Food Res 57(1):71–83. doi:10.1002/mnfr.201200503
Chimento A, Casaburi I, Rosano C, Avena P, De Luca A, Campana C, Martire E, Santolla MF, Maggiolini M, Pezzi V, Sirianni R (2014) Oleuropein and hydroxytyrosol activate GPER/GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. Mol Nutr Food Res 58(3):478–489. doi:10.1002/mnfr.201300323
Toteda G, Lupinacci S, Vizza D, Bonofiglio R, Perri E, Bonofiglio M, Lofaro D, La Russa A, Leone F, Gigliotti P, Cifarelli RA, Perri A (2016) High doses of hydroxytyrosol induce apoptosis in papillary and follicular thyroid cancer cells. J Endocrinol Invest. doi:10.1007/s40618-016-0537-2
Charoenprasert S, Mitchell A (2012) Factors influencing phenolic compounds in table olives (Olea europaea). J Agric Food Chem 60(29):7081–7095. doi:10.1021/jf3017699
Visioli F, Galli C (1994) Oleuropein protects low density lipoprotein from oxidation. Life Sci 55(24):1965–1971
Borthwick LA, Corris PA, Mahida R, Walker A, Gardner A, Suwara M, Johnson GE, Moisey EJ, Brodlie M, Ward C, Perry JD, De Soyza A, Mann DA, Fisher AJ (2013) TNFalpha from classically activated macrophages accentuates epithelial to mesenchymal transition in obliterative bronchiolitis. Am J Transplant 13(3):621–633. doi:10.1111/ajt.12065
Miyajima A, Kosaka T, Seta K, Asano T, Umezawa K, Hayakawa M (2003) Novel nuclear factor kappa B activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction. J Urol 169(4):1559–1563. doi:10.1097/01.ju.0000045686.21766.c1
Dulundu E, Ozel Y, Topaloglu U, Toklu H, Ercan F, Gedik N, Sener G (2007) Grape seed extract reduces oxidative stress and fibrosis in experimental biliary obstruction. J Gastroenterol Hepatol 22(6):885–892. doi:10.1111/j.1440-1746.2007.04875.x
Das S, Becker BN, Hoffmann FM, Mertz JE (2009) Complete reversal of epithelial to mesenchymal transition requires inhibition of both ZEB expression and the Rho pathway. BMC Cell Biol 10:94. doi:10.1186/1471-2121-10-94
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S. Lupinacci and G. Toteda have contributed equally to this work.
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Lupinacci, S., Toteda, G., Vizza, D. et al. Active compounds extracted from extra virgin olive oil counteract mesothelial-to-mesenchymal transition of peritoneal mesothelium cells exposed to conventional peritoneal dialysate: in vitro and in vivo evidences. J Nephrol 30, 841–850 (2017). https://doi.org/10.1007/s40620-016-0368-4
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DOI: https://doi.org/10.1007/s40620-016-0368-4