Abstract
Zinc (Zn) plays an important role in preventing many types of epithelial-to-mesenchymal transition (EMT)-driven fibrosis in vivo. But its function in the EMT of the peritoneal mesothelial cells (PMCs) remains unknown. Here, we studied the Zn effect on the high glucose (HG)-induced EMT in the rat PMCs (RPMCs) and the underlying molecular mechanisms. We found that Zn supplementation significantly inhibited TGF-β1 and ROS production, and attenuated the HG-induced EMT in the RPMCs, likely through inhibition of MAPK, NF-κB, and TGF-β/Smad pathways.
Similar content being viewed by others
Abbreviations
- RPMCs:
-
Rat peritoneal mesothelial cells
- HG:
-
High glucose
- CAPD:
-
Continuous ambulatory peritoneal dialysis
- EMT:
-
Epithelial-to-mesenchymal transition
- MAPK:
-
Mitogen-activated protein kinase
- JNK:
-
Jun N-terminal kinase
- MTT:
-
3-[4,5-Dimethylthiazol-2-y]-2,5-diphenyltetrazolium bromide
- DMEM:
-
Dulbecco’s modified Eagle medium
- DMSO:
-
Dimethyl sulfoxide
- SMA:
-
Smooth muscle cell actin
- FITC:
-
Fluorescein isothiocyanate
- TPEN:
-
N,N,N′,N′-Tetrakis(2-pyridylmethyl) ethylenediamine
- RIPA:
-
Radioimmune precipitation assay
- TGF:
-
Transforming growth factor
- PBS:
-
Phosphate-buffered saline
- DCF-DA:
-
2,7-Dichlorofluorescein diacetate
- TBS:
-
Tris-buffered saline
References
Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, Dominguez-Jimenez C, Jimenez-Heffernan JA et al (2003) Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 348:403–413
Margetts PJ, Bonniaud P, Liu L, Hoff CM, Holmes CJ, West-Mays JA et al (2005) Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 16:425–436
Chung SH, Stenvinkel P, Bergstrom J, Lindholm B (2000) Biocompatibility of new peritoneal dialysis solutions: what can we hope to achieve? Perit Dial Int 20(Suppl 5):S57–S67
Ha H, Yu MR, Lee HB (2001) High glucose-induced PKC activation mediates TGF-beta 1 and fibronectin synthesis by peritoneal mesothelial cells. Kidney Int 59:463–470
Cendoroglo M, Sundaram S, Jaber BL, Pereira BJ (1998) Effect of glucose concentration, osmolality, and sterilization process of peritoneal dialysis fluids on cytokine production by peripheral blood mononuclear cells and polymorphonuclear cell functions in vitro. Am J Kidney Dis 31:273–282
Yao Q, Pawlaczyk K, Ayala ER, Styszynski A, Breborowicz A, Heimburger O et al (2008) The role of the TGF/Smad signaling pathway in peritoneal fibrosis induced by peritoneal dialysis solutions. Nephron Exp Nephrol 109:e71–e78
Yu MA, Shin KS, Kim JH, Kim YI, Chung SS, Park SH et al (2009) HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium. J Am Soc Nephrol 20:567–581
Ksiazek K, Breborowicz A, Jorres A, Witowski J (2007) Oxidative stress contributes to accelerated development of the senescent phenotype in human peritoneal mesothelial cells exposed to high glucose. Free Radic Biol Med 42:636–641
Noh H, Kim JS, Han KH, Lee GT, Song JS, Chung SH et al (2006) Oxidative stress during peritoneal dialysis: implications in functional and structural changes in the membrane. Kidney Int 69:2022–2028
Vallee BL (1995) The function of metallothionein. Neurochem Int 27:23–33
Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118
Takahashi M, Saito H, Higashimoto M, Hibi T (2007) Possible inhibitory effect of oral zinc supplementation on hepatic fibrosis through downregulation of TIMP-1: a pilot study. Hepatol Res 37:405–409
Wang L, Zhou Z, Saari JT, Kang YJ (2005) Alcohol-induced myocardial fibrosis in metallothionein-null mice: prevention by zinc supplementation. Am J Pathol 167:337–344
Gandhi MS, Deshmukh PA, Kamalov G, Zhao T, Zhao W, Whaley JT et al (2008) Causes and consequences of zinc dyshomeostasis in rats with chronic aldosteronism. J Cardiovasc Pharmacol 52:245–252
Van Biervliet S, Vande Velde S, Van Biervliet JP, Robberecht E (2008) The effect of zinc supplements in cystic fibrosis patients. Ann Nutr Metab 52:152–156
Mansouri K, Halsted JA, Gombos EA (1970) Zinc, copper, magnesium and calcium in dialyzed and nondialyzed uremic patients. Arch Intern Med 125:88–93
Thomson NM, Stevens BJ, Humphery TJ, Atkins RC (1983) Comparison of trace elements in peritoneal dialysis, hemodialysis, and uremia. Kidney Int 23:9–14
Zima T, Tesar V, Mestek O, Nemecek K (1999) Trace elements in end-stage renal disease. 1. Methodological aspects and the influence of water treatment and dialysis equipment. Blood Purif 17:182–186
Padovese P, Gallieni M, Brancaccio D, Pietra R, Fortaner S, Sabbioni E et al (1992) Trace elements in dialysis fluids and assessment of the exposure of patients on regular hemodialysis, hemofiltration and continuous ambulatory peritoneal dialysis. Nephron 61:442–448
Wang AY, Sea MM, Ip R, Law MC, Chow KM, Lui SF et al (2002) Independent effects of residual renal function and dialysis adequacy on dietary micronutrient intakes in patients receiving continuous ambulatory peritoneal dialysis. Am J Clin Nutr 76:569–576
Hjelle JT, Golinska BT, Waters DC, Steidley KR, McCarroll DR, Dobbie JW (1989) Isolation and propagation in vitro of peritoneal mesothelial cells. Perit Dial Int 9:341–347
Simonian MH, Smith JA (2006) Spectrophotometric and colorimetric determination of protein concentration. Curr Protoc Mol Biol Chapter 10: Unit 10 11A
Liu Q, Mao H, Nie J, Chen W, Yang Q, Dong X et al (2008) Transforming growth factor {beta}1 induces epithelial-mesenchymal transition by activating the JNK-Smad3 pathway in rat peritoneal mesothelial cells. Perit Dial Int 28(Suppl 3):S88–S95
Prasad AS (2008) Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontol 43:370–377
Bao S, Knoell DL (2006) Zinc modulates cytokine-induced lung epithelial cell barrier permeability. Am J Physiol Lung Cell Mol Physiol 291:L1132–L1141
Mengheri E, Nobili F, Vignolini F, Pesenti M, Brandi G, Biavati B (1999) Bifidobacterium animalis protects intestine from damage induced by zinc deficiency in rats. J Nutr 129:2251–2257
Fernandez-Madrid F, Prasad AS, Oberleas D (1973) Effect of zinc deficiency on nucleic acids, collagen, and noncollagenous protein of the connective tissue. J Lab Clin Med 82:951–961
Lee HB, Yu MR, Song JS, Ha H (2004) Reactive oxygen species amplify protein kinase C signaling in high glucose-induced fibronectin expression by human peritoneal mesothelial cells. Kidney Int 65:1170–1179
Oteiza PI, Olin KL, Fraga CG, Keen CL (1995) Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes. J Nutr 125:823–829
Ho E, Ames BN (2002) Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci USA 99:16770–16775
Bao B, Prasad AS, Beck FW, Snell D, Suneja A, Sarkar FH et al (2008) Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Transl Res 152:67–80
Corniola RS, Tassabehji NM, Hare J, Sharma G, Levenson CW (2008) Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Res 1237:52–61
Yamaguchi M, Kishi S (1995) Differential effects of transforming growth factor-beta on osteoclast-like cell formation in mouse marrow culture: relation to the effect of zinc-chelating dipeptides. Peptides 16:1483–1488
Szuster-Ciesielska A, Plewka K, Daniluk J, Kandefer-Szerszen M (2009) Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling. Biochem Pharmacol 78:301–314
Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17:548–558
Cannito S, Novo E, di Bonzo LV, Busletta C, Colombatto S, Parola M (2010) Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease. Antioxid Redox Signal 12:1383–1430
Auwardt RB, Mudge SJ, Chen CG, Power DA (1998) Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells. J Am Soc Nephrol 9:1620–1628
Uzzo RG, Leavis P, Hatch W, Gabai VL, Dulin N, Zvartau N et al (2002) Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. Clin Cancer Res 8:3579–3583
Ho E, Quan N, Tsai YH, Lai W, Bray TM (2001) Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice. Exp Biol Med (Maywood) 226:103–111
Meerarani P, Reiterer G, Toborek M, Hennig B (2003) Zinc modulates PPARgamma signaling and activation of porcine endothelial cells. J Nutr 133:3058–3064
Kim CH, Kim JH, Lee J, Ahn YS (2003) Zinc-induced NF-kappaB inhibition can be modulated by changes in the intracellular metallothionein level. Toxicol Appl Pharmacol 190:189–196
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, X., Wang, J., Fan, Y. et al. Zinc Supplementation Attenuates High Glucose-Induced Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells. Biol Trace Elem Res 150, 229–235 (2012). https://doi.org/10.1007/s12011-012-9451-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-012-9451-4