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Effects of cadmium and uranium on some in vitro renal targets

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Abstract

Metals are major pollutants not only in occupational settings but also in the general environment. Chronic exposure of workers has been related to severe damage, especially at the renal level. While toxic compounds such as metals are well known to severely impair tubular functions, it is clear that nephrotoxicants can act on various other renal targets, i.e., vascular and glomerular ones.In vitro models are available to assess these toxicities and can be used to better understand the different cell targets. This paper summarizes data obtained in our laboratory after exposure of isolated renal structures such as glomeruli, and cell cultures such as glomerular mesangial and tubular epithelial cells, to cadmium and uranium. Morphometric studies by image analysis of isolated glomeruli and mesangial cultured cells showed that cadmium and uranium induced a dose- and time-dependent glomerular contraction accompanied by disorganization of the cytoskeleton. Classical viability tests demonstrated various factors influencing the metal toxicity. The important roles of pH, extracellular protein concentrations and the nature of the anion accompanying the metal were demonstrated. These data obtained inin vitro models provide better understanding of the cytotoxicity after metal uptake and accumulation in glomerular and tubular cells. Moreover, the glomerular and tubular cytotoxicity they induce may be correlated with severe renal hemodynamic changes in vivo. Finally, we briefly present eventual improvements forin vitro renal models by the use of new cell models such as immortalized human cell lines or by the introduction of porous supports and perifusion devices.

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References

  • Abel J, Hohr D, Schurek HJ. Renal handling of cadmium and cadmium-metallothionein: studies on the isolated perfused rat kidney. Arch Toxicol. 1987; 60: 370–5.

    Article  PubMed  CAS  Google Scholar 

  • Ahn DW, Kim YM, Kim KR, Park YS. Cadmium binding and sodium-dependent solute transport in renal brush border membrane vesicles. Toxicol Appl Pharmacol. 1999; 154: 212–18.

    Article  PubMed  CAS  Google Scholar 

  • Anthony ML, Gartland K, Beddell CR, Lindon JC, Nichlson JK. Studies of the biochemical toxicology of uranyl nitrate in the rat. Arch Toxicol. 1994; 68: 43–53.

    Article  PubMed  CAS  Google Scholar 

  • Avasthi PS, Evan P, Hay D. Glomerular endothelial cells in uranyl nitrate induced acute renal failure in rats. J Clin Invest. 1980; 65: 121–7.

    Article  PubMed  CAS  Google Scholar 

  • Barrouillet MP, Potier M, Cambar J. Cadmium nephrotoxicity assessed in isolated rat glomeruli and cultured mesangial cells; evidence for contraction of glomerular cells. Exp Nephrol. 1999a; 7: 251–8.

    Article  PubMed  CAS  Google Scholar 

  • Barrouillet MP, Moiret A, Cambar J. Protective effects of polyphenols against cadmium-induced glomerular mesangial cell myocontracture. Arch Toxicol. 1999b; 73: 485–8.

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharyya MH, Breitenstein BD, Muggenburg BA, Metivier H, Stradling GN, Volfu V. Traitement de la contamination interne accidentelle des travailleurs. Collection IPSN. Les Ulis: France: EDP Sciences; 1995.

    Google Scholar 

  • Blais A, Morvan-Baleynaud J, Friedlander G, Le Grimellec C. Primary culture of rabbit proximal tubules as a cellular model to study nephrotoxicity of xenobiotics. Kidney Int. 1993; 44: 13–8.

    PubMed  CAS  Google Scholar 

  • Bohets HH, Nouwen EJ, DeBroe ME, Dierickx PJ. Effects of ftal calf serum on cell viability, cytotoxicity and detoxi¢ca-tion in the two kidney derived cell lines LLC-PK1 and MDCK. Toxicol In Vitro. 1994; 8: 559–61.

    Article  Google Scholar 

  • Bracken WM, Sharma RP, Klelinschuster SJ. Cadmium accumulation and subcellular distribution in relation to cadmium chloride induced cytotoxicity in vitro. Toxicology. 1984; 33: 93–102.

    Article  PubMed  CAS  Google Scholar 

  • Brady HR, Kone BC, Brenner RM, Gullans SR. Early effects of uranyl nitrate on respiration and K+ transport in rabbit proximal tubule. Kidney Int. 1989; 36(1): 27–34.

    PubMed  CAS  Google Scholar 

  • Buchet J, Lauwerys R, Roels H, et al. Renal effect of cadmium on body burden of general population. Lancet. 1990; 336: 699–702.

    Article  PubMed  CAS  Google Scholar 

  • Castaing N, Merlet D, Cambar J. Les me¨thodes d'e¨valuation in vitro de la ne¨phrotoxicite¨. J Toxicol Clin Exp. 1990; 10: 73–87.

    PubMed  CAS  Google Scholar 

  • Chaudhari A, Kirschenbraum MA. Altered glomerular eiconanoid biosynthesis in uranyl nitrate-induced acute renal failure. Biochim Biophys Acta. 1984; 792(2): 135–40.

    PubMed  CAS  Google Scholar 

  • Chauvin MF, Bolon C, Conjard A, et al. Advantages and limitations of the use of isolated kidney tubules in pharmacotoxicology. Cell Biol Toxicol. 1996; 12: 283–7.

    Article  PubMed  CAS  Google Scholar 

  • Dawson DC, Ballatori N. Membrane transporters as sites of action and routes of entry for toxic metals. In: Goyer RA and Cherian MG eds. Toxicology of metals: biochemical aspects. Berlin: Springer-Verlag; 1995; 115: 53–76.

    Google Scholar 

  • Diamond GL. Biological consequences of exposure to soluble forms of natural uranium. Radiat Prot Dosim. 1989; 24: 23–33.

    Google Scholar 

  • Diamond GL, Zalups RK. Understanding renal toxicity of heavy metals. Toxicol Pathol. 1998; 26: 92–103.

    Article  PubMed  CAS  Google Scholar 

  • Dorian C, Gattone V, Klaassen C. Renal cadmium deposition and injury as a result of accumulation of cadmium-metal-lothionein by the proximal convoluted tubules. A light microscopic autography study with 109Cd. Toxicol Appl Pharmacol. 1992; 114: 173–81.

    Article  PubMed  CAS  Google Scholar 

  • Durbin PW, Kuligreen B, Xu J, Raymond KN. New agents for in vivo chelation of uranium(VI): e¤cacy and toxicity in mice of multidentate catecholate and hydroxypyridonate ligands. Health Phys. 1997; 72: 865–79.

    Article  PubMed  CAS  Google Scholar 

  • Elinder CG. Normal values for cadmium in human tissue, blood, and urine in different countries. In: Friberg L, Elinder CG, Kjellstrom, Nordberg GF, eds. Cadmium and health; a toxicological and epidemiological appraisal. Vol. I. Boca Raton, FL: CRC Press; 1985: 81–102.

    Google Scholar 

  • Endo T, Kimura O, Sakatta M. Comparative study of cadmium and mercury accumulation by LLC-PK1 cells: effects of pH on uptake and e¥ux. Toxicol Lett. 1996; 89: 131–7.

    Article  Google Scholar 

  • Endo T, Kimura O, Hatakeyama M, Takada M, Sakata M. Effects of zinc and copper on cadmium uptake by brush border membrane vesicles. Toxicol Lett. 1997; 91: 111–20.

    Article  PubMed  CAS  Google Scholar 

  • Endo T, Kimura O, Sakata M. Bidirectional transport of cadmium across apical membrane of renal epithelial cell lines via H+-antiporter and inorganicanion exc hanger. Toxicology. 1998; 131: 183–92.

    Article  PubMed  CAS  Google Scholar 

  • Foulkes EC. On the mechanism of transfer of heavy metals across cell membranes. Toxicology. 1988; 52: 263–72.

    Article  PubMed  CAS  Google Scholar 

  • Foulkes EC. Transport of toxicheavy metals acell membranes. ProcSocExp Bio Med. 2000; 223: 234–40.

    Article  CAS  Google Scholar 

  • Friberg L, Piscator M, Nordberg GF, Kjellstrom T. Cadmium and the environment, 2nd edn. Cleveland, OH: CRC Press; 1974: 23–91.

    Google Scholar 

  • Friberg L, Elinder CG, Kjellstrom T, Nordberg GF. In: Friberg L, Elinder CG, Kjellstrom T, Nordberg GF, eds. Cadmium and health; a toxicological and epidemiological appraisal. Vol. II. Boca Raton, FL: CRC Press; 1986.

    Google Scholar 

  • Galle P. Roª le des lysosomes et des mitochrondries dans les phe¨nome© nes de concentration et d'e¨limination d'e¨le¨ments mine¨raux (uranium et or) par le rein. J Microsc. 1974; 19: 17–24.

    CAS  Google Scholar 

  • Gilman AP, Villeneuve DC, Secours VE, et al. Uranyl nitrate: 28-day and 91-day toxicity studies in Sprague-Dawley rat. Toxicol Sci. 1998; 41: 117–28.

    Article  PubMed  CAS  Google Scholar 

  • Goering PL, Waalkes MP, Klaassen CD. Toxicology of cadmium. In: Goyer RA and Cherian MG, eds. Toxicology of metals: biochemical aspects. Berlin: Springer-Verlag; 1995; 115: 189–214.

    Google Scholar 

  • Grouselle M, Boudou A, Oreja-Erroz B. Me¨thode de mesure des £ux entrant de cadmium par titration du Fura-2 a© l'e¨chelle d'une cellule MDCK. Etude par vide¨o-microscopie de £uorescence. CR Acad Sci Paris. 1996: 319: 277–87.

    CAS  Google Scholar 

  • Haley DP, Bulger RE, Dobyan DC. The long-term effects of uranyl nitrate on the structure and function of the rat kidney. Virchows Arch B Cell Pathol Incl Mol Pathol. 1982; 41: 181–92.

    PubMed  CAS  Google Scholar 

  • Hazen-Martin DJ, Sens DA, Blackburn JG, Sens, MA. Cadmium nephrotoxicity in human proximal tubule cell cultures. In Vitro Cell Dev Biol. 1989; 25: 784–90.

    PubMed  CAS  Google Scholar 

  • Henge¨-Napoli MH, Ansoborlo E, Chazel V, Houpert P, Paquet F, Gourmelon P. E¤cacy of EHBP for the decorporation of uranium after intramuscular contamination in rats. Int J Radiat Biol. 1999; 75: 113–7.

    Google Scholar 

  • Henge¨-Napoli MH, L'Azou B, Be¨rard P, Cambar J. Toxicite¨de l'Uranium. In: Me¨tivier H, ed. L'Uranium de l'environe-ment a© l'homme. Paris: EDP Sciences IPSN-Collection 2001a: 239–60.

    Google Scholar 

  • Henge¨-Napoli MH. Traitement des contaminations par de l'Uranium. In: Me¨tivier H, ed. L'Uranium de l'environe-ment a© l'homme. Paris: EDP Sciences IPSN-Collection; 2001b: 261–79.

    Google Scholar 

  • Herak-Kramberger CM, Sabolic I. The integrity of renal cortical brush-border and basolateral membrane vesicles is damaged in vitro by nephrotoxicheavy metals. Toxicology. 2001; 156: 139–47.

    Article  PubMed  CAS  Google Scholar 

  • Hirsch GH. Differential effects of nephrotoxic agents on renal transport and metabolism by use of in vitro techniques. Environ Health Perspect. 1976; 15: 89–99.

    PubMed  CAS  Google Scholar 

  • IARC. Beryllium, cadmium, mercury and exposures in the glass manufacturing industry. In: Monographs on the evaluation of the carcinogenic risks to humans. Lyon: International Agency for Research on Cancer; 1993; 58: 119–237.

    Google Scholar 

  • Jarup L, Elinder CG, Spang G. Cumulative blood-cadmium and tubular proteinuria: a dose–response relationship. Arch Occup Environ Health. 1988; 60: 223–9.

    Article  CAS  Google Scholar 

  • Kaiji T, Suzuki M, Yamamoto C, et al. Sensitive response of cultured vascular smooth-muscle cells to cadmium cytotoxicity: comparaison with cultured vascular endothelial cells and kidney epithelial LLC-PK1 cells. Toxicol Lett. 1996; 89: 131–97.

    Article  Google Scholar 

  • Kastner S, Soose M, Stolte H. Human kidney cells in in vitro pharmaco-toxicology. In: Rogiers V, Sonck W, Shephard E, Vercruysse A, eds. Human cells in in vitro pharmacotoxicology. Brussels: VUB Press; 1993: 197–238.

    Google Scholar 

  • Kawada T, Koyama H, Suzuki S. Cadmium, NAG activity and 2-microglobulin in the urine of cadmium pigment workers. Br J Ind Med. 1989; 46: 52–5.

    PubMed  CAS  Google Scholar 

  • Kim YK, Choi JK, Kim JS, Park YS. Changes in renal function in cadmium-intoxicated rats. Pharmacol Toxicol. 1988; 63: 342–50.

    PubMed  CAS  Google Scholar 

  • Kjellstrom T. Renal effects. In: Friberg L, Elinder CG, Kjellstrom T, Nordberg GF, eds. Cadmium and health: effect and response. A toxicological and epidemiological appraisal. Vol II. Boca Raton, FL: CRC Press; 1985: 21–109.

    Google Scholar 

  • Kjellstrom T. Itai-Itai disease. In: Friberg L, Elinder CG, Kjellstrom T, Nordberg GF, eds. Cadmium and health: a toxicological and epidemiological appraisal. Vol II. Boca Raton, FL: CRC Press; 1986: 257–90.

    Google Scholar 

  • Kobayashi S, Nagase M, Honda N, Hishida A. Glomerular alterations in uranyl acetate-induced acute renal failure in rabbits. Kidney Int. 1984; 26: 808–15.

    PubMed  CAS  Google Scholar 

  • Lagroye I, L'Azou B, Lakhdar B, Plande J, Cambar J. Nephrotoxicite¨in vitro: mode© les glome¨rulaires. In: Adolphe M, Guillouzo A, Marano F, eds. Toxicologie cellulaire in vitro: me¨thodes et applications, Paris: Editions de l'INSERM; 1995: 121–50.

    Google Scholar 

  • Lauwerys R, Buchet JP, Roels H, Brouwers J, Stanescu D. Epidemiological survey of workers exposed to cadmium: effect on lung, kidney and several biological indices. Arch Environ Health. 1974; 28: 145–8.

    PubMed  CAS  Google Scholar 

  • L'Azou B, Cambar J. Prevention of cyclosporin-induced vasoconstriction in rat isolated glomeruli with pharmacological vasoactive agents. Toxicol In Vitro. 1993; 7: 417–20.

    Article  Google Scholar 

  • L'Azou B, Lakhdar B, Cambar J. Use of two in vitro models to study the renal vasoreactivity of cyclosporin. Transpl Proc. 1994; 26: 2883–5.

    Google Scholar 

  • L'Azou B, Medina J, Frieauff W, Cordier A, Cambar J, Wolf A. In vitro models to study mechanisms involved in cyclosporine A mediated glomerular contraction. Arch Toxicol. 1999; 73: 337–45.

    Article  PubMed  Google Scholar 

  • Lopez R, Diaz Sylvester PL, Ubios AM, Cabrini RL. Percutanous toxicity of uranyl nitrate: its effect in terms of exposure area and time. Health Phys. 2000; 78(4): 434–7.

    Article  PubMed  CAS  Google Scholar 

  • Matsuura K, Takasugi M, Kunifuji Y, HoricA, Kuroiwa A. Morphological effects of cadmium on proximal tubular cells in rats. Biol Trace Elem Res. 1991; 31: 171–82.

    Article  PubMed  CAS  Google Scholar 

  • McDonald-Taylor CK, Singh A, Gilman A. Uranyl nitrate-induced proximal tubule alterations in rabbits: a quantitative analysis. Toxicol Pathol. 1997; 25: 381–9.

    PubMed  CAS  Google Scholar 

  • Mesna OJ, Wilhelmsen TW, Andersen RA. Correlations between cadmium treatment, oxygen uptake and metallothionein response in liver and kidney from two mice strains. Comp Biochem Physiol Biochem Mol Biol. 2000; 125: 114–20.

    Article  Google Scholar 

  • Me¨tivier H, Ansoborlo E, Chazel V, Ge¨rasimo P. Biocine¨tique et dosime¨trie des expositions a© l'uranium. In: Me¨tivier H, ed. L'Uranium de l'environement a© l'homme. Paris: EDP Sciences IPSN-Collection; 2001: 213–38.

    Google Scholar 

  • Mingard F, Diezi J. Cadmium uptake by brush border membrane vesicles from rabbit renal external cortex. J Trace Elem Electrolytes Dis. 1992; 6: 111–5.

    CAS  Google Scholar 

  • Minuth WW, Steiner P, Strehl R, Schumacher K, De Vries U, Kloth S. Modulation of cell differentiation in perfusion culture. Exp Nephrol. 1999; 7: 394–406.

    Article  PubMed  CAS  Google Scholar 

  • Mirto H, Barrouillet MP, Henge-Napoli MH, Ansoborlo E, Fournier M, Cambar J. Uranium-induced vasoreactivity in isolated glomeruli and cultured rat mesangial cells. Toxicol In Vitro. 1999a; 13: 707–11.

    Article  CAS  Google Scholar 

  • Mirto H, Barrouillet MP, Henge-Napoli MH, Ansoborlo E, Fournier M, Cambar J. In£uence of uranium (VI) speciation for the evaluation of in vitro uranium cytotoxicity on LLC-PK1 cell. Hum Exp Toxicol. 1999b; 18: 180–7.

    Article  PubMed  CAS  Google Scholar 

  • Mirto H, Henge-Napoli MH, Gibert R, Ansoborlo E, Fournier M, Cambar J. Intracellular behaviour of uranium (VI) on renal epithelial cells in culture (LLC-PK1): in£uence of uranium speciation. Toxicol Lett. 1999c; 104: 249–56.

    Article  PubMed  CAS  Google Scholar 

  • Nizet A. In£uence of uranyl nitrate upon tubular reabsorption and glomerular ¢ltration in blood perfused isolated dog kidneys. P£ugers Arch. 1981; 391: 249–56.

    Google Scholar 

  • Nolan CV, Shaikh ZA. The vascular endothelium as a target tissue in acute cadmium toxicity. Life Sci. 1986; 39: 1403–9.

    Article  PubMed  CAS  Google Scholar 

  • Piscator M. Long-term observations on tubular and glomerular function in cadmium exposed persons. Environ Health Perspect. 1984; 54: 175–9.

    PubMed  CAS  Google Scholar 

  • Priest ND. Toxicity of depleted uranium. Lancet. 2001; 357: 244–5

    Article  PubMed  CAS  Google Scholar 

  • Robinson MK, Barfuss DW, Zalups RK. Cadmium transport andtoxicityin isolatedperfused segments of the renal proximal tubule. Toxicol Appl Pharmacol. 1993; 121: 103–11.

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Barbero A, L'Azou B, Cambar J, Lopez-Novoa JM. Potential use of isolated glomeruli and cultured mesangial cells as in vitro models to assess nephrotoxicity. Cell Biol Toxicol. 2000; 16: 145–53.

    Article  PubMed  CAS  Google Scholar 

  • Stoeppler M. Cadmium. In: Merian E, ed. Metals and their compounds in the environment. New York: VCH; 1991: 803–51.

    Google Scholar 

  • Suzuki CA, Cherian MG. Effects of cadmium-metallothionein on renal organicion transport and lipid peroxidation in rats. J Biochem Toxicol. 1988; 3: 11–20.

    PubMed  CAS  Google Scholar 

  • Syversen T. Factors important to the quality of cell culture. Toxicology ATLA. 1991; 19: 234–6.

    Google Scholar 

  • Tanigawara Y, Saito Y, Aiba T, Ohoka K, Kamiya A, Hori R. Moment analysis of drug disposition in kidney: transport of p-aminohippurate and tetraethylammonium in the perfused kidney isolated from uranyl nitrate-induced acute renal failure rats. J Pharm Sci. 1990; 79: 249–56.

    PubMed  CAS  Google Scholar 

  • Taylor DM, Taylor SK. Environmental uranium and human health. Rev Environ Health. 1997; 12: 147–57.

    PubMed  CAS  Google Scholar 

  • Templeton DM. Cadmium uptake by cells of renal origin. J Biol Chem. 1990; 265(35): 21764–70.

    PubMed  CAS  Google Scholar 

  • Templeton DM, Chaitu N. Effects of divalent metals on the isolated rat glomerulus. Toxicology. 1990; 61: 119–33.

    Article  PubMed  CAS  Google Scholar 

  • Templeton DM, Sheepers J. Effects on Ni and Cd on proteoglycan synthesis by the isolated glomerulus and glomerular cells in culture. In: Bach PM, Gregg NJ, eds. Nephrotoxicity. New York: Dekker; 1991; 57: 377–82.

    Google Scholar 

  • Thun MJ, Baker DB, Steeland K, Smith AB, Halperin W, Berl T. Renal toxicity in uranium mill workers. Scand J Work Environ Health. 1985; 11: 83–90.

    PubMed  CAS  Google Scholar 

  • Toutain H. Ne¨phrotoxicite¨in vitro: mode© les de cultures de cellules tubulaires re¨nales. In: Adolphe M, Guillouzo A, Marano F, eds. Toxicologie cellulaire in vitro: me¨thodes et applications. Paris: Editions de l'INSERM; 1995: 151–89.

    Google Scholar 

  • Toutain H, Morin JP. Renal proximal tubule cell cultures for studying drug-induced nephrotoxicity and modulation of phenotype expression by medium components. Ren Fail. 1992; 14: 371–83.

    PubMed  CAS  Google Scholar 

  • Vandewalle A.Stimulated secretion of lysosomal enzymes induced by drugs in transimmortalized proximal tubule mouse kidney cells. Cell Biol Toxicol. 1996; 12: 299–303.

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Templeton DM. Cellular factors mediate cadmium-dependent actin depolymerization. Toxicol Appl Pharmacol. 1996; 139: 115–21.

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Chin TA, Templeton DM. Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells. Cell Motil Cytoskeleton. 1996; 33: 208–22.

    Article  PubMed  CAS  Google Scholar 

  • Wilkes MF, Kwizera EN, Bach PH. Assessment of heavy metal nephrotoxicity in vitro using isolated rat glomeruli and proximal tubular fragments. Ren Physiol Biochem. 1990; 13: 275–84.

    Article  Google Scholar 

  • Zamora ML, Tracy BL, Zielinski JM, Meyerhof DP, Moss MA. Chronicingestion of uranium in drinking water: a study of kidney bioeffects in humans. Toxicol Sci. 1998; 43(1): 68–77.

    Article  PubMed  CAS  Google Scholar 

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  1. Laboratoire de Biologie Cellulaire, UFR de Pharmacie, Université Victor-Ségalen, Bordeaux, France

    B. L'Azou, L. Minaro, M.-P. Barrouillet & J. Cambar

  2. Nucléaire/DPHP/SDOS, Institut de Protection et de Sûreté, Fontenay aux Roses, France

    M.-H. Henge-Napoli & H. Mirto

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  1. B. L'Azou
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L'Azou, B., Henge-Napoli, MH., Minaro, L. et al. Effects of cadmium and uranium on some in vitro renal targets. Cell Biol Toxicol 18, 329–340 (2002). https://doi.org/10.1023/A:1019536115152

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