The aim of this study was to determine if there are sex-related differences in the acute kidney injury induced by HgCl 2 since female rats express lower levels of renal Oat1 and Oat3 (transporters involved in renal uptake of mercury) as compared with males. Control males and females and Hg-treated male and female Wistar rats were employed. Animals were treated with HgCl 2 (4 mg/kg body weight (b.w.), intraperitoneal (i.p.)) 18 h before the experiments. HgCl 2 induced renal impairment both in male and female rats. However, female rats showed a lower renal impairment than male rats. The observed increase in kidney weight/body weight ratio seen in male and female rats following HgCl 2 treatment was less in the female rats. Urine volume and creatinine clearance decreased and Oat5 urinary excretion increased in both males and females, but to a lesser degree in the latter. Urinary alkaline phosphatase (AP) activity and histological parameters were modified in male but not in female rats after HgCl 2 administration. These results indicate that the lower Oat1 and Oat3 expression in the kidney of females restricts Hg uptake into renal cells protecting them from this metal toxicity. These gender differences in renal injury induced by mercury are striking and also indicate that Oat1 and Oat3 are among the main transporters responsible for HgCl 2-induced renal injury.
References
[1]
WHO. Inorganic Mercury. In Environmental Health Criteria; World Health Organization: Geneva, Switzerland; Volume 118, p. 1991.
[2]
Vahter, M.; Akesson, A.; Lind, B.; Bj?rs, U.; Schütz, A.; Berglund, M. Longitudinal study of methylmercury and inorganic mercury in blood and urine of pregnant and lactating women, as well as umbilical cord blood. Environ. Res 2000, 84, 186–194.
[3]
McRill, C.; Boyer, L.V.; Flood, T.J.; Ortega, L. Mercury toxicity due to the use of a cosmetic cream. J. Occup. Environ. Med 2000, 42, 4–7.
Hultman, P.; Nielsen, J.B. The effect of dose, gender, and non-H-2 genes in murine mercury-induced autoimmunity. J. Autoimm 2001, 17, 27–37.
[6]
Akesson, I.; Schutz, A.; Attewell, R.; Skerfving, S.; Glantz, P.O. Status of mercury and selenium in dental personnel: Impact of amalgam work and own fillings. Arch. Environ. Health 1991, 46, 102–109.
[7]
Thomas, D.J.; Fisher, H.L.; Sumler, M.R.; Mushak, P.; Hall, I.I. Sexual differences in the excretion of organic and inorganic mercury by methyl mercury-treated rats. Environ. Res 1987, 43, 203–227.
[8]
Grandjean, P.; Weihe, P.; White, R.F.; Debes, F. Cognitive performance of children preferentially exposed to “safe” levels of methylmercury. Environ. Res 1998, 77, 165–172.
[9]
McKeown-Eyssen, G.E.; Ruedy, J.; Neims, A. Methyl mercury exposure in northern Quebec. II. Neurologic findings in children. Am. J. Epidemiol 1983, 118, 470–479.
[10]
Gimenez-Llort, L.; Ahlbom, D.; Daré, E.; Vahter, M.; Ogren, S.; Ceccatelli, S. Prenatal exposure to methylmercury changes dopamine-modulated motor activity during early ontogeny: Age and gender-dependent effects. Environ. Toxicol. Pharmacol 2001, 9, 61–70.
[11]
Rossi, A.D.; Ahlbom, E.; Ogren, S.O.; Nicotera, P.; Ceccatelli, S. Prenatal exposure to methylmercury alters locomotor activity of male but not female rats. Exp. Brain. Res 1997, 117, 428–436.
[12]
Vahter, M.; Akesson, A.; Lidén, C.; Seccatelli, S.; Berglund, M. Gender differences in the disposition and toxicity of metals. Environ. Res 2007, 104, 85–95.
[13]
Emanuelli, T.; Rocha, J.B.T.; Pereira, M.E.; Porciúncula, L.O.; Morsch, V.M.; Martins, A.F.; Souza, D.O. Effect of mercuric chloride intoxication and dimercaprol treatment on σ-aminolevulinate dehydratase from brain, liver and kidney of adult mice. Pharmacol. Toxicol 1996, 79, 136–143.
[14]
Tanaka-Kagawa, T.; Suzuki, M.; Naganuma, A.; Yamanaka, N.; Imura, N. Strain difference in sensitivity of mice to renal toxicity of inorganic mercury. J. Pharmacol. Exp. Ther 1998, 285, 335–341.
[15]
Zalups, R.K. Molecular interactions with mercury in the kidney. Pharmacol. Rev 2000, 52, 113–143.
[16]
Bridges, C.C.; Zalups, R.K. Transport of inorganic mercury and methylmercury in target tissues and organs. J. Toxicol. Environ. Health Crit. Rev 2010, 13, 385–410.
[17]
Zalups, R.K. Basolateral uptake of mercuric conjugates of N-acetylcysteine and cysteine in the kidney involves the organic anion transport system. J. Toxicol. Environ. Health 1998, 53, 615–636.
[18]
Bridges, C.C.; Zalups, R.K. Molecular and ionic mimicry and the transport of toxic metals. Toxicol. Appl. Pharmacol 2005, 204, 274–308.
[19]
Bridges, C.C.; Joshee, L.; Zalups, R.K. Multidrug resistance proteins and the renal elimination of inorganic mercury mediated by 2,3-dimercaptopropane-1-sulfonic acid and meso-2,3-dimercaptosuccinic acid. J. Pharmacol. Exp. Ther 2008, 324, 383–390.
[20]
Torres, A.M.; Dnyanmote, A.V.; Bush, K.T.; Wu, W.; Nigam, S.K. Deletion of multispecific organic anion transporter (Oat1/Slc22a6) protects from mercury-induced kidney injury. J. Biol. Chem 2011, 286, 26391–26395.
[21]
Buist, S.C.; Klaassen, C.D. Rat and mouse differences in gender-predominant expression of organic anion transporter (Oat1-3; Slc22a6-8) mRNA levels. Drug Metab. Dispos 2004, 32, 620–625.
[22]
Cerrutti, J.A.; Brandoni, A.; Quaglia, N.B.; Torres, A.M. Sex differences is p-aminohippuric acid transport in rat kidney: Role of membrane fluidity and expression of OAT1. Mol. Cell. Biochem 2002, 233, 175–179.
[23]
Ljubojevic, M.; Herak-Kramberger, C.M.; Hagos, Y.; Dahn, A.; Endou, H.; Burckhardt, G.; Sabolic, I. Rat renal cortical Oat1 and Oat3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. Am. J. Physiol 2004, 287, F124–F138.
[24]
Cerrutti, J.A.; Quaglia, N.B.; Torres, A.M. Characterization of the mechanisms involved in the gender differences in p-aminohippurate renal elimination in rats. Can. J. Physiol. Pharmacol 2001, 79, 805–813.
[25]
Munger, K.; Baylis, C. Sex differences in renal hemodynamics in rats. Am. J. Physiol 1988, 254, F223–F231.
[26]
Remuzzi, A.; Puntorieri, S.; Mazzoleni, A.; Remuzzi, G. Sex related differences in glomerular ultrafiltration and proteinuria in Munich-Wistar rats. Kidney Int 1988, 34, 481–486.
[27]
Heiene, R.; Moe, L.; Moelmen, G. Calculation of urinary enzyme excretion, with renal structure and function in dogs with pyometra. Res. Vet. Sci 2001, 70, 129–137.
Di Giusto, G.; Anzai, N.; Endou, H.; Torres, A.M. Oat5 and NaDC1 protein abundance in kidney and urine after renal ischemic reperfusion injury. J. Histochem. Cytochem 2009, 57, 17–27.
[30]
Di Giusto, G.; Torres, A.M. Organic anion transporter 5 renal expression and urinary excretion in rats exposed to mercuric chloride: A potential biomarker of mercury-induced nephropathy. Arch. Toxicol 2010, 84, 741–749.
[31]
Stacchiotti, A.; Ricci, F.; Rezzani, R.; Volti, G.L.; Borsani, E.; Lavazza, A.; Bianchi, R.; Rodella, L.F. Tubular stress proteins and nitric oxide synthase expression in rat kidney exposed to mercuric chloride and melatonin. J. Histochem. Cytochem 2006, 54, 1149–1157.
[32]
Nava, M.; Romero, F.; Quiroz, Y.; Parra, G.; Bonet, L.; Rodriguez-Iturbe, B. Melatonin attenuates acute renal failure and oxidative stress induced by mercuric chloride in rats. Am. J. Physiol 2000, 279, 910–918.
[33]
Di Giusto, G.; Anzai, N.; Ruiz, M.L.; Endou, H.; Torres, A.M. Expression and function of Oat1 and Oat3 in rat kidney exposed to mercuric chloride. Arch. Toxicol 2009, 83, 887–897.
[34]
Wright, S.H.; Dantzler, W.H. Molecular and cellular physiology of renal organic cation and anion transport. Physiol. Rev 2004, 84, 987–1049.
[35]
Anzai, N.; Kanai, Y.; Endou, H. Organic anion transporter family: Current knowledge. J. Pharmacol. Sci 2006, 100, 411–426.
[36]
Rizwan, A.N.; Burckhardt, G. Organic anion transporters of the SLC22 family: Biopharmaceutical, physiological, and pathological roles. Pharm. Res 2007, 24, 450–470.
[37]
Kojima, R.; Sekine, T.; Kawachi, M.; Cha, S.H.; Suzuki, Y.; Endou, H. Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. J. Am. Soc. Nephrol 2002, 13, 848–857.
[38]
Villar, S.R.; Brandoni, A.; Torres, A.M. Time course of organic anion excretion in rats with bilateral ureteral obstruction: Role of organic anion transporters (Oat1 and Oat3). Nephron. Physiol 2008, 110, 45–56.
[39]
Di Giusto, G.; Anzai, N.; Endou, H.; Torres, A.M. Elimination of organic anions in response to an early stage of renal ischemia-reperfusion in rat: Role of basolateral plasma membrane transporter and cortical renal blood flow. Pharmacology 2008, 81, 127–136.
[40]
Wen, J.G.; Frokiaer, J.; Jorgensen, T.M. Obstructive nephropathy. An update of the experimental research. Urol. Res 1999, 27, 29–39.
[41]
Green, J.; Abassi, Z.; Winaver, J.; Skorecki, K.L. Acute Renal Failure: Clinical and Pathophysiologic Aspects. In The Kidney: Physiology and Pathophysiology, 3rd ed; Seldin, D.W., Giebisch, G., Eds.; Williams & Wilkins: Lippincott, PA, USA, 2000; pp. 2329–2373.
[42]
Brady, H.R.; Brenner, B.M.; Lieberthal, W. Acute Renal Failure. In Brenner & Rector’s the Kidney, 7th ed; Brenner, B.M., Rector, F.C., Eds.; W.B. Saunders Company: PA, USA, 2004; pp. 1215–1292.
[43]
Institute of Laboratory Animal Resources. Guide for the Care and Use of Laboratory Animals, 7th ed ed.; National Academy Press: Washington, DC, USA; p. 1996.
[44]
Jensen, R.E.; Berndt, W.O. Epinephrine and norepinephrine enhance p-aminohippurate transport into basolateral membrane vesicles. J. Pharmacol. Exp. Ther 1988, 244, 543–549.
[45]
Villar, S.R.; Brandoni, A.; Anzai, N.; Endou, H.; Torres, A.M. Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction. Kidney Int 2005, 68, 2704–2713.
[46]
Sedmak, J.J.; Grossberg, S.E. A rapid, sensitive and versatile assay for protein using Coomassie Brillant Blue G250. Anal. Biochem 1977, 79, 544–552.
[47]
Anzai, N.; Jutabha, P.; Enomoto, A.; Yokoyama, H.; Nonoguchi, H.; Hirata, T.; Shiraya, K.; He, X.; Cha, S.H.; Takeda, M.; et al. Functional characterization of rat organic anion transporter 5 (Slc22a19) at the apical membrane of renal proximal tubules. J. Pharmacol. Exp. Ther 2005, 315, 534–544.