Single Exposure of Mesothelial Cells to Glucose Degradation Products (GDPs) Yields Early Advanced Glycation End-Products (AGEs) and a Proinflammatory Response
Restricted accessReview articleFirst published online May, 2003
Single Exposure of Mesothelial Cells to Glucose Degradation Products (GDPs) Yields Early Advanced Glycation End-Products (AGEs) and a Proinflammatory Response
Fluids commonly used for peritoneal dialysis (PD) have a low pH and a high glucose content. Furthermore, heat sterilization of dialysis fluids degrades some of the glucose into glucose degradation products (GDPs), such as methylglyoxal (MGO) and 3-deoxyglucosone (3-DG). Mesothelial cells (MCs) form the first line in the peritoneal cavity and are constantly exposed to these nonphysiological conditions. Since MCs play an important role in the regulation of inflammatory responses in the peritoneal cavity, we studied the kinetics of MC uptake of highly purified GDP species, along with their effect on various cellular biological and immunological parameters.
← Methods
Methylglyoxal and 3-DG were purified and added to MC cultures. Complexing to medium components or uptake by MCs was analyzed over time by HPLC of the culture supernatant and by immunocytochemistry of MCs for MGO-modified proteins. Furthermore, MCs were exposed to a single dose of MGO or 3-DG and analyzed for apoptosis, proliferation by MTT assay, and [3H]-thymidine incorporation. Incorporation of [35S]-methionine was determined in order to analyze de novo protein synthesis. Expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), CD44, and vascular cell adhesion molecule-1 (VCAM-1) was analyzed by cell-bound ELISA. Effects of MGO and 3-DG on cytokine production were also analyzed.
← Results
Substitution of MGO and 3-DG in culture medium resulted in a spontaneous decrease in MGO over time, whereas 3-DG levels decreased minimally. The concentration of these GDPs was more reduced in the presence of MCs, indicating binding to and/or uptake by MCs of these GDPs. Mesothelial cells that had been cultured in the presence of MGO showed positive staining with a monoclonal that specifically recognizes MGO-modified proteins, demonstrating complexing to mesothelial cellular proteins. Cell-bound ELISA showed a two- to threefold induction of expression of VCAM-1 by MGO and 3-DG; the expression of ICAM-1 and CD44 was not changed. Mesothelial cells showed a twofold increase in interleukin (IL)-6 and IL-8 production after exposure to 3-DG. Furthermore, incubation with MGO and 3-DG induced apoptosis and reduced the proliferation of cells, but did not influence protein synthesis.
← Conclusions
In the current report we demonstrate that MCs take up MGO and 3-DG and form early advanced glycation end-products. Upon short exposure to a single GDP, MCs react with enhanced cytotoxic damage and a proinflammatory response, evidenced by increased VCAM-1 expression and elevated production of IL-6 and IL-8.
DobbieJ.W., LloydJ.K., GallC.A.Categorization of ultrastructural changes in peritoneal mesothelium, stroma and blood vessels in uremia and CAPD patients.Adv Perit Dial1990; 6: 3–12.
2.
Di PaoloN., GarosiG., PetriniG., MonaciG.Morphological and morphometric changes in mesothelial cells during peritoneal dialysis in the rabbit.Nephron1996; 74: 594–9.
3.
MateijsenM.A., van der WalA.C., HendriksP.M., ZweersM.M., MulderJ., StruijkD.G.Vascular and interstitial changes in the peritoneum of CAPD patients with peritoneal sclerosis.Perit Dial Int1999; 19: 517–25.
4.
WangT., QureshiA.R., HeimbürgerO., WaniewskiJ., BergströmJ., LindholmB.Daily exposure to dialysis fluid results in changes in peritoneal transport.Perit Dial Int1997; 17: 379–86.
VisserC.E., TekstraJ., Brouwer–SteenbergenJ.J., TukC.W., BoorsmaD.M., Sampat–SardjoepersadS.C.Chemokines produced by mesothelial cells: Hugro-alpha, IP-10, MCP-1 and RANTES.Clin Exp Immunol1998; 112: 270–5.
7.
TekstraJ., VisserC.E., TukC.W., Brouwer–SteenbergenJ.J., BurgerC.W., KredietR.T.Identification of the major chemokines that regulate cell influxes in peritoneal dialysis patients.J Am Soc Nephrol1996; 7: 2379–84.
8.
ZeillemakerA.M., MulF.P., Hoynck van PapendrechtA.A., KuijpersT.W., RoosD., LeguitP.Polarized secretion of interleukin-8 by human mesothelial cells: A role in neutrophil migration.Immunology1995; 84: 227–32.
9.
JonjicN., PeriG., BernasconiS., SciaccaF.L., ColottaF., PelicciP.Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells.J Exp Med1992; 176: 1165–74.
10.
KleinC.L., BittingerF., SkarkeC.C., WagnerM., KohlerH., WalgenbachS.Effects of cytokines on the expression of cell adhesion molecules by cultured human omental mesothelial cells.Pathobiology1995; 63: 204–12.
11.
LiF.K., DavenportA., RobsonR.L., LoetscherP., RothleinR., WilliamsJ.D.Leukocyte migration across human peritoneal mesothelial cells is dependent on directed chemokine secretion and ICAM-1 expression.Kidney Int1998; 54: 2170–83.
12.
ZeillemakerA.M., MulF.P., Hoynck van PapendrechtA.A., LeguitP., VerbrughH.A., RoosD.Neutrophil adherence to and migration across monolayers of human peritoneal mesothelial cells. The role of mesothelium in the influx of neutrophils during peritonitis.J Lab Clin Med1996; 127: 279–86.
13.
HendersonI.S., CouperI.A., LumsdenA.Potentially irritant glucose metabolites in unused CAPD fluid. In: WinchesterJ.W., ed. Frontiers in Peritoneal Dialysis.New York: Field, Rich and Associates;1986: 261–4.
14.
Nilsson–ThorellC.B., MuscaluN., AndrenA.H., KjellstrandP.T., WieslanderA.P.Heat sterilization of fluids for peritoneal dialysis gives rise to aldehydes.Perit Dial Int1993; 13: 208–13.
15.
SchalkwijkC.G., PosthumaN., ten BrinkH.J., ter WeeP.M., TeerlinkT.Induction of 1,2-dicarbonyl compounds, intermediates in the formation of advanced glycation end-products, during heat-sterilization of glucose-based peritoneal dialysis fluids.Perit Dial Int1999; 19: 325–33.
16.
LindenT., ForsbackG., DeppischR., HenleT., WieslanderA.3-Deoxyglucosone, a promoter of advanced glycation end products in fluids for peritoneal dialysis.Perit Dial Int1998; 18: 290–3.
17.
WitowskiJ., KorybalskaK., WisniewskaJ., BreborowiczA., GahlG.M., FreiU.Effect of glucose degradation products on human peritoneal mesothelial cell function.J Am Soc Nephrol2000; 11: 729–39.
18.
WieslanderA., LindenT.Glucose degradation and cytotoxicity in PD fluids.Perit Dial Int1996; 16(Suppl 1): S114–18.
19.
SundaramS., CendorogloM., CookerL.A., JaberB.L., FaictD., HolmesC.J.Effect of two-chambered bicarbonate lactate-buffered peritoneal dialysis fluids on peripheral blood mononuclear cell and polymorphonuclear cell function in vitro.Am J Kidney Dis1997; 30: 680–9.
20.
JonassonP., BraideM.Kinetics and dose response of the effects of heated glucose peritoneal dialysis fluids on the respiratory burst of rat peritoneal leukocytes.ASAIO J2000; 46: 469–73.
21.
HekkingL.H.P., ZareieM., DriesprongB.A.J., FaictD., WeltenA.G.A., de GreeuwI.Better preservation of peritoneal morphology and defense in the rat after long-term exposure to a bicarbonate/lactate solution.J Am Soc Nephrol2001; 12: 2775–86.
22.
LageC., PischetsriederM., AufrichtC., JörresA., SchillingH., Passlick–DeetjenJ.First in vitro and in vivo experiences with Stay-Safe Balance, a pH-neutral solution in a dual-chambered bag.Perit Dial Int2000; 20(Suppl 5): S28–32.
23.
LoT.W., SelwoodT., ThornalleyP.J.The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins.Biochem Pharmacol1994; 48: 1865–70.
24.
EdelsteinD., BrownleeM.Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine.Diabetes1992; 41: 26–9.
25.
LambE.J., CattellW.R., DawnayA.B.In vitro formation of advanced glycation end products in peritoneal dialysis fluid.Kidney Int1995; 47: 1768–74.
26.
DawnayA.Advanced glycation end products in peritoneal dialysis.Perit Dial Int1996; 16(Suppl 1): S50–3.
27.
MiyataT., SugiyamaS., SaitoA., KurokawaK.Reactive carbonyl compounds related uremic toxicity (“carbonyl stress”).Kidney Int Suppl2001; 78: S25–31.
28.
NakayamaM., KawaguchiY., YamadaK., HasegawaT., TakazoeK., KatohN.Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible pathophysiological role in CAPD.Kidney Int1997; 51: 182–6.
29.
ShawS., AkyolM., BellJ., BriggsJ.D., DominiczakM.H.Effects of continuous ambulatory peritoneal dialysis and kidney transplantation on advanced glycation endproducts in the skin and peritoneum.Cell Mol Biol (Noisy-le-grand)1998; 44: 1061–8.
30.
McLellanA.C., ThornalleyP.J.Synthesis and chromatography of 1,2-diamino-4,5-dimethoxybenzene, 6,7-dimethoxy-2-methylquinoxaline and 6,7-dimethoxy-2,3-dimethylquinoxaline for use in a liquid chromatographic fluorimetric assay of methylglyoxal.Anal Chim Acta1992; 263: 137–42.
31.
KhademH.E., HortonD., MeshrekiM.H., NashedM.A.New route for the synthesis of 3-deoxyaldos-2-uloses.Carbohydr Res1971; 17: 183–92.
32.
StylianouE., JennerL.A., DaviesM., ColesG.A., WilliamsJ.D.Isolation, culture and characterization of human peritoneal mesothelial cells.Kidney Int1990; 37: 1563–70.
33.
van de LoosdrechtA.A., BeelenR.H., OssenkoppeleG.J., BroekhovenM.G., LangenhuijsenM.M.A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia.J Immunol Methods1994; 174: 311–20.
34.
KangY., EdwardsL.G., ThornalleyP.J.Effect of methylglyoxal on human leukaemia 60 cell growth: Modification of DNA G1 growth arrest and induction of apoptosis.Leuk Res1996; 20: 397–405.
35.
OkadoA., KawasakiY., HasuikeY., TakahashiM., TeshimaT., FujiiJ.Induction of apoptotic cell death by methylglyoxal and 3-deoxyglucosone in macrophage-derived cell lines.Biochem Biophys Res Commun1996; 225: 219–24.
36.
BoulangerE., WautierM.P., WautierJ.L., BovalB., PanisY., WernertN.AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression.Kidney Int2002; 61: 148–56.
37.
HoriO., YanS.D., OgawaS., KuwabaraK., MatsumotoM., SternD.The receptor for advanced glycation end-products has a central role in mediating the effects of advanced glycation end-products on the development of vascular disease in diabetes mellitus.Nephrol Dial Transplant1996; 11(Suppl 5): S13–16.
38.
KislingerT., FuC., HuberB., QuW., TaguchiA., DuY.S.N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression.J Biol Chem1999; 274: 31740–9.
39.
WitowskiJ., ThielA., DechendR., DunkelK., FouquetN., BenderT.O.Synthesis of C-X-C and C-C chemokines by human peritoneal fibroblasts: Induction by macrophage-derived cytokines.Am J Pathol2001; 158: 1441–50.
40.
WitowskiJ., WisniewskaJ., KorybalskaK., BenderT.O., BreborowiczA., GahlG.M.Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal mesothelial cells.J Am Soc Nephrol2001; 12: 2434–41.
41.
WestwoodM.E., ThornalleyP.J.Induction of synthesis and secretion of interleukin 1 beta in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation end-products.Immunol Lett1996; 50: 17–21.
