Advertisement

Archives of Toxicology

, Volume 80, Issue 7, pp 387–393 | Cite as

Nephrotoxicity of uranyl acetate: effect on rat kidney brush border membrane vesicles

  • M. Goldman
  • A. Yaari
  • Z. Doshnitzki
  • R. Cohen-Luria
  • A. Moran
Inorganic Compounds

Abstract

Since the Gulf war exposure to depleted uranium, a known nephrotoxic agent, there is a renewed interest in the toxic effects of uranium in general and its mechanism of nephrotoxicity which is still largely unknown in particular. In order to investigate the mechanism responsible for uranium nephrotoxicity and the therapeutic effect of urine alkalization, we utilized rat renal brush border membrane vesicles (BBMV). Uranyl acetate (UA) caused a decrease in glucose transport in BBMV. The apparent K i of uranyl was 139±30 μg uranyl/mg protein of BBMV. Uranyl at 140 μg/mg protein of BBMV reduced the maximal capacity of the system to transport glucose [V max 2.2±0.2 and 0.96±0.16 nmol/mg protein for control and uranyl treated BBMV (P<0.001), respectively] with no effect on the apparent K m (1.54±0.33 and 1.54±0.51 mM for control, and uranyl treated BBMV, respectively). This reduction in V max is at least partially due to a decrease in the number of sodium-coupled glucose transporters as apparent from the reduction in phlorizin binding to the uranyl treated membranes, V max was reduced from 247±13 pmol/mg protein in control BBMV to 119±3 pmol/mg protein in treated vesicles (P<0.001). The pH of the medium has a profound effect on the toxicity of UA on sodium-coupled glucose transport in BBMV: higher toxicity at neutral pH (around pH 7.0), and practically no toxicity at alkaline pH (7.6). This is the first report showing a direct inhibitory dose and pH dependent effect of uranyl on the glucose transport system in isolated apical membrane from kidney cortex.

Keywords

Brush border membrane vesicles Uranyl acetate Glucose transport Nephrotoxicity 

References

  1. Ben-Nun A, Cohen-Luria R, Potashnik RNB, Moran A (1993) Cystine loading induces Fanconi’s syndrome in rats; in vivo and vesicles studies. Am J Physiol Renal Fluid 265:F839–F844Google Scholar
  2. Berner W, Kinne R (1976) Transport of p-aminohippuric acid by plasma membrane vesicles isolated from rat kidney cortex. Pfuegers Arch 361:269–277CrossRefGoogle Scholar
  3. Biber J, Stieger B, Haase W, Murer H (1981) A high yield preparation for rat kidney brush border membranes. Different behaviour of lysosomal markers. Biochem Biophys Acta 647:169–176PubMedCrossRefGoogle Scholar
  4. Brady HR, Kone BC, Brenner RM, Gullans SR (1989) Early effects of uranyl nitrate on respiration and K+ transport in rabbit proximal tubule. Kidney Int 36:27–34PubMedCrossRefGoogle Scholar
  5. Esmann M (1979) ATPase and phosphatase activity of Na+,K+-ATPase: molar and specific activity, protein determination. Methods enzymol 156:105–115CrossRefGoogle Scholar
  6. Fiske CH, SubbaRow Y (1925) The colorimetric determination of phosphorous. J Biol Chem 66:375–400Google Scholar
  7. Hori R, Takano M, Okano T, Inui K-I (1985) Transport of p-aminohippurate, tetramehtylammonium and d-glucose in renal brush border membranes from rats with acute renal failure. J Pharmacol Exp Ther 233:776–781PubMedGoogle Scholar
  8. Kinne R, Schwartz IL (1978) Isolated membrane vesicles in evaluation of the nature, localization, and regulation of renal transport processes. Kidney Int 14:547–556PubMedCrossRefGoogle Scholar
  9. Leggett RW (1989) The behavior and chemical toxicity of U in the kidney: a reassessment. Health Phys 57:365–383PubMedCrossRefGoogle Scholar
  10. McDiarmid MA, Keogh JP, Hooper FJ, McPhaul K, Squibb K, Kane R, DiPino R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Hamilton M, Jacobson-Kram D, Burrows B, Walsh M (2000) Health effects of depleted uranium on exposed Gulf War veterans. Environ Res 82:168–180CrossRefPubMedGoogle Scholar
  11. Mirto H, Henge-Napoli MH, Gibert R, Ansoborlo E, Fournier M, Cambar J (1999) Intracellular behaviour of uranium(VI) on renal epithelial cell in culture (LLC-PK1): influence of uranium speciation. Toxicol Lett 104:249–256CrossRefPubMedGoogle Scholar
  12. Moran A, Davis LR, Turner RJ (1988) High affinity phlorizin binding to the LLC-PK1 exhibits a sodium:phlorizin stochiometry of 2:1. J Biol Chem 263:187–192PubMedGoogle Scholar
  13. Murer H, Biber J, Gmaj P, Stieger B (1984) Cellular mechanism in epithelial transport: advantages and disadvantages of studies with vesicles. Mol Physiol 6:55–82Google Scholar
  14. NCRP (1989) Management of persons accidentally contaminated with radionuclides. National Council on Radiation Protection and MeasurementsGoogle Scholar
  15. Nechay BR, Thompson JD, Saunders JP (1980) Inhibition by uranyl nitrate of adenosine triphosphatases derived from animal and human tissues. Toxicol Appl Pharmacol 53:410–419CrossRefPubMedGoogle Scholar
  16. Pellmar TC, Fuciarelli AF, Ejnik JW, Hamilton M, Hogan J, Strocko S, Emond C, Mottaz HM, Landauer MR (1999) Distribution of uranium in rats implanted with depleted uranium pellets. Toxicol Sci 49:29–39CrossRefPubMedGoogle Scholar
  17. Priest ND (2001) Toxicity of depleted uranium. Lancet 357:244–246CrossRefPubMedGoogle Scholar
  18. Turner RJ (1983) Quantitative studies of cotransport systems: models and vesicles. J Membr Biol 76:1–15CrossRefPubMedGoogle Scholar
  19. Turner RJ, Moran A (1982a) Further studies of proximal tubule brush border membrane d-glucose transport heterogeneity. J Membr Biol 70:37–45CrossRefGoogle Scholar
  20. Turner RJ, Moran A (1982b) Stochiometric studies of renal outer cortical brush border membrane d-glucose transporter. J Membr Biol 67:73–80CrossRefGoogle Scholar
  21. Turner RJ, Moran A (1982c) Heterogeneity of sodium dependent d-glucose transport sites along the proximal tubule: Evidence from vesicles studies. Am J Physiol 242:F406–F414Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • M. Goldman
    • 2
  • A. Yaari
    • 1
  • Z. Doshnitzki
    • 3
  • R. Cohen-Luria
    • 1
    • 4
  • A. Moran
    • 1
  1. 1.Department of Physiology, Faculty of Health SciencesBen-Gurion University of the NegevBeer-ShevaIsrael
  2. 2.Department of PediatricsAssaf Harofeh Medical CenterZerifinIsrael
  3. 3.Department of Diagnostic ImagingAssaf Harofeh Medical CenterZerifinIsrael
  4. 4.Department of ChemistryBen Gurion University of the NegevBeer-ShevaIsrael

Personalised recommendations