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Cellular mechanisms of nephrotoxicity

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Clinical Nephrotoxins

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Abstract

The kidney is uniquely susceptible to the effect of toxins. Factors which contribute to this vulnerability include: (1) A generous blood flow that is disproportionate compared to other organs of the body which results in the delivery of a high dose of the toxin, (2) The substantial glomerular and tubular surface areas provide continuous opportunity for absorption into the cell, (3) Tubular transport systems that are both site and substrate specific provide additional pathways for enhanced cellular uptake, (4) The countercurrent medullary concentrating mechanism provides a dual mechanism which increases the luminal concentration of nonreabsorbable compounds while allowing the concentration of compounds trapped within the renal interstitium to increase, (5) Various enzymatic processes within renal cells convert either parent compounds or non-toxic intermediate metabolites into toxic metabolites or toxic by-products, (6) Finally, the high rate of metabolic activity which characterizes renal tubular cells makes them vulnerable to oxygen deprivation. Despite these factors, it has long been appreciated that toxic injury to the kidney occurs in a patchy fashion suggesting that injury is often compartmentalized with in the kidney.

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References

  1. Mudge GH. Pathogenesis of nephrotoxicity: Pharmacological principles. In: Bach PH, Lock EA, editors. Renal heterogeneity and target cell toxicity. Chichester: John Wiley & Sons, 1985; 1–12.

    Google Scholar 

  2. Walker RJ, Duggins GG. Cellular mechanisms of drug nephrotoxicity. In: Seldin DW, Giebisch G, editors. The kidney physiology and pathophysiology. 2nd Edition. New York: Raven Press, 1992; 3571–95.

    Google Scholar 

  3. Goldstein RS. Biochemical heterogeneity and site-specific tubular injury. In: Hook JB, Goldstein RS, editors. Toxicology of the kidney, 2nd edition. New York: Raven Press Ltd, 1993;201–47.

    Google Scholar 

  4. Zenser TV, Mattammal MB, Brown WW, Davies BD. Enzyme systems involved in the formation of reactive metabolites in the renal medulla: cooxidation via prostaglandin H synthase. Fundam Appl Toxicol 1984; 4: 922–9.

    PubMed  CAS  Google Scholar 

  5. Davis BB, Mattammal MB, Zenser TV. Renal metabolism of drugs and xenobiotics. Nephron 1981; 27: 187–96.

    PubMed  CAS  Google Scholar 

  6. Zenser TV, Mattammal MB, Brown WW, Davies BD. Cooxygenation by prostaglandin cyclooxygenase from rabbit inner medulla. Kidney Int 1979; 16: 688–94.

    PubMed  CAS  Google Scholar 

  7. Zenser TV, Mattammal MB, Brown WW, Davies BD. Effect of aspirin on metabolism of acetaminophen and benzidine by renal inner medulla prostaglandin hydroperoxidase. J Clin Lab Med 1983; 101: 58–65.

    CAS  Google Scholar 

  8. Zenser TV, Mattammal MB, Brown WW, Davies BD. Differential distribution of mixed function oxidase activities inn rabbit kidneys. J Pharmacol Exp Ther 1979; 207: 719–25.

    Google Scholar 

  9. Meister A. Glutathione metabolism and its selective modification. J Biol Chem 1988; 263: 17205–8.

    PubMed  CAS  Google Scholar 

  10. Rush GF, Smith JH, Newton JF, Hook JB. Chemically induced nephrotoxicity: Role of metabolic activation. CRC Crit Rev Toxicol 1986; 13: 99–160.

    Google Scholar 

  11. Potter DW, Hinson JA. Reactions of N-acetyl-p-benzo-quinoneimine with reduced glutathione, acetaminophen and NADPH. Mol Pharmacol 1986; 30: 33–41.

    PubMed  CAS  Google Scholar 

  12. Mohandas J, Marshall JJ, Duggin GG, Horvath JS, Tiller DJ. Differential distribution of glutathione and glutathione related enzymes in the rabbit kidney. Biochem Pharmacol 1984; 33: 1801–7.

    PubMed  CAS  Google Scholar 

  13. Trump BF, Berezesky IK, Lipsky MM, Jones TW. Heterogeneity of the nephron: significance to nephrotoxicity. In: Bach PH, Lock EA editors. Renal heterogeneity and target cell toxicity. Chichester: John Wiley & Sons, 1985; 31–42.

    Google Scholar 

  14. Weinberg JM. The cell biology of ischemic renal injury. Kidney Int 1991; 39: 476–500.

    PubMed  CAS  Google Scholar 

  15. Weinberg JM. The cellular basis of nephrotoxicity. In: Schrier RW, Gottschalk CW, editors. Diseases of the kidneys. Boston: Little Brown and Co., 1993; 1031–97.

    Google Scholar 

  16. Gullan SR, Hebert SC. Metabolic basis of ion transport. In: Brenner BM, Rector FC, editors. The kidney, 4th edition, vol 1 Philadelphia: WB Saunders, 1991; 76–109.

    Google Scholar 

  17. Jorgensen PL. Structure, function and regulation of Na,K-ATPase in the kidney. Kidney Int 1986; 29: 10–20.

    PubMed  CAS  Google Scholar 

  18. Vanderwalle A, Wirthensohn G, Heidrich HG, Guder WG. Distribution of hexokinase and phosphoenolcar-boxykinase along the rabbit nephron. Am J Physiol 1981; 240: F492–500.

    Google Scholar 

  19. Zager RA. Gentamicin nephrotoxicity in the setting of acute renal hypoperfusion. Am J Physiol 1988; 254: F576–81.

    Google Scholar 

  20. Rosen S, Epstein FH, Brezis M. Determinants of intrarenal oxygenation: factors in acute renal failure. Renal Failure 1992; 14: 321–5.

    PubMed  CAS  Google Scholar 

  21. Zager RA. Obstruction of proximal tubules initiates cytoresistance against hypoxic damage. Kidney Int 1995; 47: 628–37.

    PubMed  CAS  Google Scholar 

  22. Molitoris BA, Heyman C, Dahl R, Geerdes A. Mechanisms of ischemia-enhanced aminoglycoside binding and uptake by proximal tubule cells. Am J Physiol 1993; 264: F907–16.

    Google Scholar 

  23. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109–42.

    PubMed  CAS  Google Scholar 

  24. Moncada S, Higgs A. The 1-arginine-nitric oxide pathway. N Eng J Med 1993; 329: 2002–12.

    CAS  Google Scholar 

  25. Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 1991; 266: 4244–50.

    PubMed  CAS  Google Scholar 

  26. Steuhr DJ, Griffith OW Mammalian nitric oxide synthases. Adv Enzymol Relat Area Mol Biol 1992; 65: 287–346.

    Google Scholar 

  27. Jung KY, Uchida S, Endou H. Nephrotoxicity assessment by measuring cellular ATP content. 1. Substrate specificities in the maintenance of ATP content in isolated rat nephron segments. Toxicol Appl Pharmacol 1989; 100: 369–82.

    PubMed  CAS  Google Scholar 

  28. Goldstein RS, Smith PF, Tarloff JB, Contardi L, Rush GF, Hook JB. Minireview: Biochemical mechanisms of cephalorodine nephrotoxicity. Life Sci 1988; 42: 1809–16.

    PubMed  CAS  Google Scholar 

  29. Sokol PP, Ripich G, Holohan PD, Ross CD. Mechanism of ochratoxin A transport in kidney. J Pharmacol Exp Ther 1988; 246: 460–5.

    PubMed  CAS  Google Scholar 

  30. Monks TJ, Lau SS. Commentary: renal transport processes and glutathione conjugate-mediated nephrotoxicity. Drug Metab Dispos 1987; 15: 437–41.

    PubMed  CAS  Google Scholar 

  31. Burckhardt G, Ullrich KJ. Organic anion transport across the contraluminal membrane-dependence on sodium. Kidney Int 1989; 36: 370–7.

    PubMed  CAS  Google Scholar 

  32. Ullrich KJ, Rumrich G. Contraluminal transport systems in the proximal renal tubule involved in secretion of organic anions. Am J Physiol 1988; 254: F453–62.

    Google Scholar 

  33. Tarloff JB, Brand PH. Active tetraethylammonium uptake across the basolateral membrane of rabbit proximal tubule. Am J Physiol 1986; 251: F141–9.

    Google Scholar 

  34. McKinney TD. Heterogeneity of organic base secretion by proximal tubules. Am J Physiol 1982; 243: F404–7.

    Google Scholar 

  35. Sumpio BE, Maack T. Kinetics, competition, and selectivity of tubular absorption of proteins. Am J Physiol 1982; 243: F379–92.

    Google Scholar 

  36. Camargo MJF, Sumpio BE, Maack T. Renal hydrolysis of absorbed protein: influence of load and lysosomal pH. Am J Physiol 1984; 247: F656–64.

    Google Scholar 

  37. Bennett WM, Elzinga LW, Porter GA. Tubulointerstitial disease and toxic nephropathy. In: Brenner BM, Rector FCJr, editors. The Kidney. Philadelphia, WB Saunders Co, 1991: 1430–96.

    Google Scholar 

  38. Bohle A, Mackensen-Haen S, Gise H, Grund KE, Wehrmann M, Batz C, Bogenschtz O, Schmitt H, Nagy J, Müller C, Müller G. The consequences of tubuloin-terstitial changes for renal function in glomerulopathies. In: Amerio A, Cortelli P, Massry SE, editors. Tubulo-Interstitial Nephropathies. Boston, Dordrecht, London, Kluwer, 1991: 29–40.

    Google Scholar 

  39. Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 1992; 20: 1–17.

    PubMed  CAS  Google Scholar 

  40. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 1981; 241: F85–93.

    Google Scholar 

  41. Fries JWU, Sandstrom DJ, Meyer TW, Rennke HG. Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest 1989; 60: 205–18.

    PubMed  CAS  Google Scholar 

  42. Daniels BS, Hostetter TH. Adverse effects of growth in the glomerular microcirculation. Am J Physiol 1990; 258: F1409–16.

    Google Scholar 

  43. Nilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989; 35: 1257–70.

    Google Scholar 

  44. Kelly CJ, Roth DA, Meyers CM. Immune recognition and response to the renal interstitium. Kidney Int 1991; 31: 518–30.

    Google Scholar 

  45. Ong ACM, Fine LG. Tubular-derived growth factors and cytokines in the pathogenesis of tubulointerstitial fibrosis: implications for human renal disease progression. Am J Kidney Dis 1994; 23: 205–9.

    PubMed  CAS  Google Scholar 

  46. Segal R, Fine LG. Polypeptide growth factors and the kidney. Kidney Int 1989; 36: S2–10.

    Google Scholar 

  47. Rosenberg ME, Hostetter TH. Proteinuria. In: Seldin D, Geibisch G, editors. The Kidney vol 3 (2nd Ed). New York, Raven, 1992: 3039–62.

    Google Scholar 

  48. Camussi G, Tetta C, Mazzucco G, Vercellione A. The brush border of proximal tubules of normal human kidney activates the alternative pathway of the complement system in vitro. Ann NY Acad Sci 1983; 420: 321–4.

    PubMed  CAS  Google Scholar 

  49. Howard RI, Buddington B, Alfrey AC. Urinary albumin excretion, transferrin and iron excretion in diabetic patients. Kidney Int 1991; 40: 923–6.

    PubMed  CAS  Google Scholar 

  50. Madsen KM, Applegate CW, Tisher CC. Phagocytosis of erythrocytes by the proximal tubule of the rat kidney. Cell Tissue Res 1982; 226: 363–74.

    PubMed  CAS  Google Scholar 

  51. Lan HY, Peterson DJ, Atkins RC. Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis. Kidney Int 1991; 40: 425–33.

    PubMed  CAS  Google Scholar 

  52. Nath KA, Hostetter MK, Hostetter TH. Pathophysiology of chronic tubulointerstitial disease in rats: Interactions of dietary acid load, ammonia, and complement component C3. J Clin Invest 1985; 76: 667–75.

    PubMed  CAS  Google Scholar 

  53. Schoolwerth AC, Sandler RS, Hoffman PM, Klahr S. Effects of nephron reduction and dietary protein content on renal ammoniagenesis in the rat. Kidney Int 1975; 7: 397–404.

    PubMed  CAS  Google Scholar 

  54. Hostetter MK, Nath KA, Tolins JP, Hostetter TH. Ammonia, the kidney and complement component C3. Proceedings Xth Int Congress of Nephrology, Vol 1, London, England, Bailliere Tindall, 1988: 599–612.

    Google Scholar 

  55. Nath KA. Reactive oxygen species in renal injury. In: Andreucci VE, Fine LG, editors. Int Year Book of Nephrology. Boston, Dordrecht, London, Kluwer, 1991: 42–72.

    Google Scholar 

  56. Houglum K, Brenner DA, Chojkier M. D-alpha-Tocopherol inhibits collagen al(I) gene expression in cultured human fibroblasts. Modulation of constitutive collagen gene expression by lipid peroxidation. J Clin Invest 1991; 87: 2230–5.

    PubMed  CAS  Google Scholar 

  57. Schrier RW, Harris DC, Chan L, Shapiro JI, Caramelo C. Tubular hypermetabolism as a factor in the progression of chronic renal failure. Am J Kidney Dis 1988; 12: 243–9.

    PubMed  CAS  Google Scholar 

  58. Falanga V, Martin TA, Takagi H, Kirsner RS, Helfman T, Pardes J, Ochoa MS. Low oxygen tension increases mRNA levels of alpha 1 (I) procollagen in human dermal fibroblasts. J Cell Physiol 1993; 157: 408–12.

    PubMed  CAS  Google Scholar 

  59. Crabos M, Roth M, Hahn AWA, Erne P. Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts: coupling to signaling systems and gene expression. J Clin Invest 1994; 93: 2372–8.

    PubMed  CAS  Google Scholar 

  60. Halliwell B, Gutteridge JMC. Oxygen radicals in biological systems. Part B: Oxygen radicals and antioxidants. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 1990; 186: 1–97.

    PubMed  CAS  Google Scholar 

  61. Weiss SJ, Slivka A. Monocyte and granulocyte-mediated tumor cell destruction. A role for the hydrogen peroxide-myeloperoxidase chloride system. J Clin Invest 1982; 69: 255–62.

    PubMed  CAS  Google Scholar 

  62. Halliwell B, Gutteridge JMC. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem 1984; 219: 1–14.

    CAS  Google Scholar 

  63. Gutteridge JMC. The role of superoxide and hydroxyl radicals in phospholipid peroxidation catalyzed by iron salts. FEBS Lett 1982; 150: 454–8.

    PubMed  CAS  Google Scholar 

  64. Marnett L, Wlodawer P, Samuelsson B. Co-oxidation of organic substrates by the prostaglandin synthetase of sheep vesicular gland. J Biol Chem 1975; 250: 8510–7.

    PubMed  CAS  Google Scholar 

  65. Miyamoto T, Ogino N, Yamamoto S, Hayaishi O. Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J Biol Chem 1976; 251: 2629–36.

    PubMed  CAS  Google Scholar 

  66. Babior BM. Oxygen-dependent microbial killing by phagocytes. N Engl J Med 1978; 298: 659–68.

    PubMed  CAS  Google Scholar 

  67. Granger DN. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 1988; 255: H1269–75.

    Google Scholar 

  68. Linas SL, Whittenburg D, Repine JE. Role of xanthine oxidase in ischemia/reperfusion injury. Am J Physiol 1990; 258: F711–6.

    Google Scholar 

  69. Southard JH, Marsh DC, McAnulty JF, Beizer FO. Oxygen-derived free radical damage in organ preservation: activity of superoxide dismutase and xanthine oxidase. Surg 1987; 101: 566–70.

    CAS  Google Scholar 

  70. Rush GF, Maita K, Sleight SD, Hook JB. Induction of rabbit renal mixed-function oxidases by phenobarbital: cell specific ultrastructural changes in the proximal tubule. Proc Soc Exp Biol Med 1983; 172: 430–9.

    PubMed  CAS  Google Scholar 

  71. Hill DL, Shih TW, Johnston TP, Struck RF. Macro-molecular binding and metabolism of the carcinogen 1,2-dibromoethane. Cancer Res 1978; 38: 2438–42.

    PubMed  CAS  Google Scholar 

  72. Liversey JC, Anders MW. In vitro metabolism of 1,2-dihaloethanes to ethylene. Drug Metab Dispos 1979; 7: 199–203.

    Google Scholar 

  73. van Bladeren JC, Breimer DD, Mohn GR. Stereoselective activation of vicinal dihalogen compounds to mutagens by glutathione conjugation. Biochem Pharmacol 1979; 28: 2521–4.

    PubMed  Google Scholar 

  74. Mohandas J, Duggin GG, Horvath JS, Tiller DJ. Regional differences in peroxidative activation of paracetamol (acetaminophen) mediated by cytochrome P-450 and prostaglandin endoperoxide synthetase in rabbit kidney. Res Commun Chem Path Pharmacol 1984; 61: 69–79.

    Google Scholar 

  75. Monks TJ, Highet RJ, Lau SS. Oxidative cyclization, 1,4-benzothianzine formation and dimerization of 2-bromo-3-(glutathion-S-yl)hydroquinone. Mol Pharmacol 1990; 38: 121–7.

    PubMed  CAS  Google Scholar 

  76. Monks TJ, Lau SS, Highet RJ, Gillette JR. Glutathione conjugates of 2-bromohydroquinone are nephrotoxic. Drug Metab Dispos 1985; 13: 553–9.

    PubMed  CAS  Google Scholar 

  77. Monks TJ, Anders MW, Dekant W, Stevens JL, Lau SS, van Bladeren PJ. Glutathione conjugate mediated toxicities. Toxicol Appl Pharmacol 1990; 106: 1–19.

    PubMed  CAS  Google Scholar 

  78. Lau SS, Jones TW, Highet JR, Hill BA, Monks TJ. Differences in the localization and extent of the renal proximal tubular necrosis caused by mercapturic acid and glutathione conjugates of 1,4-naphtoquinone and menadione. Toxicol Appl Pharmacol 1990; 104: 334–50.

    PubMed  CAS  Google Scholar 

  79. Anderson PM, Schultze MO. Cleavage of S-(1,2-dich-lorovinyl)-L-cysteine by an enzyme of bovine origin. Arch Biochem Biophys 1965; 111: 593–602.

    PubMed  CAS  Google Scholar 

  80. Bhattacharya RK, Schultze MO. Enzymes from bovine and turkey kidneys which cleaves S-(1,2-dich-lorovinyl)-L-cysteine. Comp Biochem Physiol 1967; 22: 723–35.

    PubMed  CAS  Google Scholar 

  81. Anders MW, Lash L, Dekant W, Elfarra AA, Dohn DR. Biosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites. Crit Rev Toxicol 1988; 18: 311–41.

    PubMed  CAS  Google Scholar 

  82. Schnellmann RG, Cross TJ, Lock EA. Pentachloro-butadienyl-L-cysteine uncouples oxidative phosphorylation by dissipating the proton gradient. Toxicol Appl Pharmacol 1989; 100: 498–505.

    PubMed  CAS  Google Scholar 

  83. Nishyama S, Taguchi T, Onosaka S. Induction of zinc-thionein by estradiol and protective effects on inorganic mercury-induced renal toxicity. Biochem Pharmacol 1987; 36: 3387–91.

    Google Scholar 

  84. Aleo MD, Wyatt RD, Schnellmann RG. The role of altered mitochondrial function in citrinin-induced toxicity to rat renal proximal tubule suspensions. Toxicol Appl Pharmacol 1991; 109: 455–63.

    PubMed  CAS  Google Scholar 

  85. Aleo MD, Wyatt RD, Schnellmann RG. Mitochondrial dysfunction is an early event in ochratoxin A but not oosporein toxicity to rat renal proximal tubules. Toxicol Appl Pharmacol 1991; 107: 73–80.

    PubMed  CAS  Google Scholar 

  86. Brazy PC, Balaban RS, Gullans SR, Mandel LJ, Dennis VW. Inhibition of renal metabolism. Relative effects of arsenate on sodium, phosphate and glucose transport by the rabbit proximal tubule. J Clin Invest 1980; 66: 1211–21.

    PubMed  CAS  Google Scholar 

  87. Carafoli E, Tiozzo R, Pasquali-Ronchetti I, Laschi R. A study of Ca2+ metabolism in kidney mitochondria during acute uranium intoxication. Lab Invest 1971; 25: 516–27.

    PubMed  CAS  Google Scholar 

  88. Jacobs EE, Jacob M, Sanadi DR, Bradley LB. Uncoupling of oxidative phosphorylation by cadmium ion. J Biol Chem 1956; 223: 147–56.

    PubMed  CAS  Google Scholar 

  89. Reynolds ES, Tannen RL, Tyler HR. The renal lesion in Wilson’s disease. Am J Med 1966; 40: 518–27.

    Google Scholar 

  90. Tune BM, Fravert D. Cephalosporin nephrotoxicity. Transport, cytotoxicity and mitochondrial toxicity of cephaloglycin. J Pharmacol Exp Ther 1980; 215: 186–90.

    PubMed  CAS  Google Scholar 

  91. Humes HD, Weinberg JM. Cellular energetics in acute renal failure. In: Brenner BM, Lazarus, editors. Acute Renal Failure. Philadelphia, WB Saunders, 1983: 47–98.

    Google Scholar 

  92. McDowell EM. Light and electron microscopic studies of the rat kidney after administration of inhibitors of the citric acid cycle in vivo. 1. Effects of sodium fluoroacetate on the proximal convoluted tubule. Am J Pathol 1972; 66: 513–42.

    PubMed  CAS  Google Scholar 

  93. Worthen HG. Renal toxicity of maleic acid in the rat: enzymatic and morphologic observation. Lab Invest 1963; 12: 791–801.

    PubMed  CAS  Google Scholar 

  94. Simmons CF Jr, Bogusky RT, Humes HD. Inhibitory effects of gentamicin on renal cortical mitochondrial oxidative phosphorylation. J Pharmacol Exp Ther 1980; 214: 709–15.

    PubMed  CAS  Google Scholar 

  95. Gordon JA, Gattone VH. Mitochondrial alterations in cisplatin-induced acute renal failure. Am J Physiol 1986; 250: F991–8.

    Google Scholar 

  96. Phelps JS, Gandolfi AJ, Brendel K, Dorr RT. Cisplatin nephrotoxicity: in vitro studies with precision-cut rabbit renal cortical slices. Toxicol Appl Pharmacol 1987; 90: 501–12.

    PubMed  CAS  Google Scholar 

  97. Gullan SR, Brady HR, Kone BC, Giebisch G, Zeidel ML. Lipid peroxidation: a consequence of cisplatin-induced free radical formation in proximal tubule but not inner medullary collecting duct cells. Kidney Int 1990; 37: 483.

    Google Scholar 

  98. Turrens JF, McCord JM. Mitochondrial generation of reactive oxygen species. In: Zelenok GB, editor. Clinical Ischemic Syndromes. Mechanisms and consequences of tissue injury. St Louis, Mosby, 1990; 203.

    Google Scholar 

  99. Gunter TE, Pfeiffer DR. Mechanisms by which mitochondria transport calcium. Am J Physiol 1990; 258: C755–86.

    Google Scholar 

  100. Nicchitta CV, Williamson JR. Spermine. A regulator of mitochondrial calcium cycling. J Biol Chem 1984; 259: 12978–3.

    PubMed  CAS  Google Scholar 

  101. Vasington FD, Murphy JV. Ca++ uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J Biol Chem 1962; 237: 2670–7.

    PubMed  CAS  Google Scholar 

  102. Lehninger AL, Rossi CS, Greenawalt JW Respiration-dependent accumulation of inorganic phosphate and Ca++ by rat liver mitochondria. Biochem Biophys Res Comm 1963; 10: 444–8.

    PubMed  CAS  Google Scholar 

  103. Beales D, Hue DP, McLean AEM. Lipid peroxidation, protein synthesis, and protection by calcium EDTA in paracetamol injury to isolated hepatocytes. Biochem Pharmacol 1985; 34: 19–23.

    PubMed  CAS  Google Scholar 

  104. Broekemeier KM, Schmid PC, Schmid HHO, Pfeiffer DR. Effects of phospholipase A2 inhibitors on ruthenium red-induced Ca2+ release from mitochondria. J Biol Chem 1985; 260: 105–13.

    PubMed  CAS  Google Scholar 

  105. Beatrice MC, Palmer JW, Pfeiffer DR. The relationship between mitochondrial membrane permeability, membrane potential, and the retention of Ca2+ by mitochondria. J Biol Chem 1980; 255: 8663–71.

    PubMed  CAS  Google Scholar 

  106. Haworth RA, Hunter DR. The Ca2+-induced membrane transition in mitochondria II. Nature of the Ca2+ trigger site. Arch Biochem Biophys 1979; 195: 460–7.

    PubMed  CAS  Google Scholar 

  107. Malis CD, Bonventre JV. Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemia and toxic mitochondrial damage. J Biol Chem 1986; 261: 14201–8.

    PubMed  CAS  Google Scholar 

  108. Brezis M, Rosen S, Silva P, Epstein FH. Renal ischemia: a new perspective. Kidney Int 1984: 26: 375–83.

    PubMed  CAS  Google Scholar 

  109. Hostetter TH, Wilkes BM, Brenner BM. Renal circulatory and nephron function in experimental acute renal failure. Philadelphia, WB Saunders, 1983: 99.

    Google Scholar 

  110. Mauk RH, Patak RV, Fadem SZ, Lifschitz MD, Stein JH. Effect of prostaglandin E administration in a nephrotoxic and vasoconstrictor model of acute renal failure. Kidney Int 1971; 12: 122–30.

    Google Scholar 

  111. Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease. Am J Pathol 1990; 136: 593–608.

    PubMed  CAS  Google Scholar 

  112. Mellgren RL. Calcium-dependent proteases: an enzyme system active at cellular membranes. FASEB J 1987; 1: 110–5.

    PubMed  CAS  Google Scholar 

  113. Trump BF, Berezesky IK, Collan Y, Kahng MW, Mergner WJ. Recent studies on the pathophysiology of ischemic cell injury. Beitr Path Bd 1976; 158: 363–81.

    CAS  Google Scholar 

  114. Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980; 68: 251–306.

    PubMed  CAS  Google Scholar 

  115. Skorecki KL, Rutledge WP, Schrier RW Acute cyclo-sporine nephrotoxicity — prototype for a renal membrane signalling disorder. Kidney Int 1992; 42: 1–10.

    PubMed  CAS  Google Scholar 

  116. Meyer-Lehnert H, Schrier RW. Cyclosporine A enhances vasopressin-induced Ca2+ mobilization and contraction in mesangial cells. Kidney Int 1988; 34: 89–97.

    PubMed  CAS  Google Scholar 

  117. Bennett WM, Elliott WC, Houghton DC, Gilbert DN, DeFehr J, McCarron DA. Reduction of experimental gentamicin nephrotoxicity in rats by dietary calcium loading. Antimicrob Agents Chemother 1982; 22: 508–512.

    PubMed  CAS  Google Scholar 

  118. Ruegg CE, Mandel LJ. Bulk isolation of renal PCT and PST. II. Differential responses to anoxia or hypoxia. Am J Physiol 1990; 259: F176–85.

    Google Scholar 

  119. Chou SY, Porush JG, Faubert PF. Renal medullary circulation: hormonal control. Kidney Int 1990; 37: 1–13.

    PubMed  CAS  Google Scholar 

  120. Lear S, Silva P, Kelley VE, Epstein FH. Prostaglandin E2 inhibits oxygen consumption in rabbit medullary thick ascending limb. Am J Physiol 1990; 258: F1372–8.

    Google Scholar 

  121. Morrissey JJ, McCracken R, Kaneto H, Vehaskari M, Montani D, Klahar S. Location of an inducible nitric oxide synthase mRNA in the normal kidney. Kidney Int 1994; 45: 998–1005.

    PubMed  CAS  Google Scholar 

  122. Brezis M, Heyman SN, Dinour D, Epstein FH, Rosen S. Role of nitric oxide in the renal medullary oxygenation: studies in isolated and intact rat kidneys. J Clin Invest 1991; 88: 390–5.

    PubMed  CAS  Google Scholar 

  123. Brezis M, Rosen S. Hypoxia of the renal medulla — its implications for disease. N Engl J Med 1995; 332: 647–55.

    PubMed  CAS  Google Scholar 

  124. Olsson RA, Pearson JD. Cardiovascular purinoceptors. Physiol Rev 1990; 70: 761–845.

    PubMed  CAS  Google Scholar 

  125. Briggs JP, Schnermann J. The tubuloglomerular feedback mechanism: functional and biochemical aspects. Ann Rev Physiol 1987; 49: 251–73.

    CAS  Google Scholar 

  126. Meister B, Fryckstedt J, Schalling M, Cortes R, Hökfelt T, Aperia A, Hemmings HC, Nairn AC, Ehrlich M, Greengard P. Dopamine- and cAMP-reg-ulated phosphoprotein (DARPP-32) and dopamine DA 1 agonist-sensitive Na +, K+-ATPase in renal tubule cells. Proc Nat Acad Sci USA 1989; 86: 8068–72.

    PubMed  CAS  Google Scholar 

  127. Bailly C, Barlet-Bas C, Amiel C. Platelet activating factor inhibits CI and K transport in the medullary thick ascending limb. Kidney Int 1992; 41: 269–74.

    PubMed  CAS  Google Scholar 

  128. Carroll MA, Sala A, Dunn CE, McGiff JC, Murphy RC. Structural identification of cytochrome P450-dependent arachidonate metabolites formed by rabbit medullary thick ascending limb cells. J Biol Chem 1991; 266: 12306–12.

    PubMed  CAS  Google Scholar 

  129. Heyman SN, Clark BA, Kaiser N, Epstein FH, Spokes K, Rosen S, Brezis M. In-vivo and in-vitro studies on the effect of amphotericin B on endothelin release. J Antimicrob Chemothera 1992; 29: 69–77.

    CAS  Google Scholar 

  130. Agmon Y, Peleg H, Greenfeld Z, Rosen S, Brezis M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994; 94: 1069–75.

    PubMed  CAS  Google Scholar 

  131. Heyman SN, Brezis M, Epstein FH, Spokes K, Silva P, Rosen S. Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991; 40: 632–42.

    PubMed  CAS  Google Scholar 

  132. Green D, Fry M, Blondin G. Phospholipids as the molecular instruments of ion and solute transport in biological membranes. Proc Nat Acad Sci USA 1980; 77: 257–61.

    PubMed  CAS  Google Scholar 

  133. Lipsky JJ, Lietman PS. Neomycin inhibition of adenosine triphosphatase: Evidence for a neomycin-phospholipid interaction. Antimicrob Agents Chemother 1980; 18: 532–5.

    PubMed  CAS  Google Scholar 

  134. Chien KR, Abrams J, Serroni A, Martin JR, Farber JL. Accelerated phospholipid degradation and associated membrane dysfunction in irreversible, ischemic liver cell injury. J Biol Chem 1978; 253: 4809–17.

    PubMed  CAS  Google Scholar 

  135. Griffith OW. The role of glutathione turnover in the apparent renal secretion of cystine. J Biol Chem 1981; 256: 12263–8.

    PubMed  CAS  Google Scholar 

  136. Matthys E, Patel Y, Kreisberg J, Stewart JH, Venkatachalam M. Lipid alterations induced by renal ischemia: pathogenic factors in membrane damage. Kidney Int 1984; 26: 153–61.

    PubMed  CAS  Google Scholar 

  137. Pfeiffer DR, Schmid PC, Beatrice MC, Schmid HHO. Intramitochondrial phospholipase activity and the effects of Ca2+ plus N-ethylmaleimide on mitochondrial function. J Biol Chem 1979; 254: 11485–94.

    PubMed  CAS  Google Scholar 

  138. Kaloyanides GJ. Metabolic interactions between drugs and renal tubulointerstitial cells: role in nephrotoxicity. Kidney Int 1991; 39: 531–40.

    PubMed  CAS  Google Scholar 

  139. Laurent G, Kishore BK, Tulkens PM. Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol 1990; 40: 2383–92.

    PubMed  CAS  Google Scholar 

  140. Kosek JC, Mazze RI, Cousins MJ. Nephrotoxicity of gentamicin. Lab Invest 1974; 30: 48–57.

    PubMed  CAS  Google Scholar 

  141. Carlier MB, Laurent G, Claes PJ, Vanderhaeghe HJ, Tulkens PM. Inhibition of lysosomal phospholipases by aminoglycosides antibiotics: in vitro comparative studies. Antimicrob Agents Chemother 1983; 23: 440–9.

    PubMed  CAS  Google Scholar 

  142. Laurent G, Carlier MB, Rollman B, VanHoof F, Tulkens PM. Mechanism of aminoglycoside-induced lysosomal phospholipidosis: in vitro and in vivo studies with gentamicin and amikacin. Biochem Pharmacol 1982; 31: 3861–70.

    PubMed  CAS  Google Scholar 

  143. Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival. Philos Trans R Soc Lond B Biol Sci 1994; 345: 265–8.

    PubMed  CAS  Google Scholar 

  144. Beeri R, Symon Z, Brezis M, Ben-Sasson SA, Baehr PH, Rosen S, Zager RA. Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys. Kidney Int 1995; 47: 1806–10.

    PubMed  CAS  Google Scholar 

  145. Ueda N, Walker PD, Hsu SM, Shah SV. Activation of a 15-kDa endonuclease in hypoxia/reoxygenation injury without morphologic features of apoptosis. Proc Natl Acad Sci USA 1995; 92: 7202–6.

    PubMed  CAS  Google Scholar 

  146. Iwata M, Myerson D, Torok-Storb B, Zager RA. An evaluation of renal tubular DNA laddering in response to oxygen deprivation and oxidant injury. J Am Soc Nephrol 1994; 5: 1307–13.

    PubMed  CAS  Google Scholar 

  147. Nouwen EJ, Verstrepen WA, Buyssens N, Zhu MQ, De Broe ME. Hyperplasia, hypertrophy, and phenotypic alterations in the distal nephron after acute proximal tubular injury in the rat. Lab Invest 1994; 70: 479–93.

    PubMed  CAS  Google Scholar 

  148. Ledda-Columbano GM, Columbano A, Coni P, Faa G, Pani P. Cell deletion by apoptosis during regression of renal hyperplasia. Am J Pathol 1989; 135: 657–62.

    PubMed  CAS  Google Scholar 

  149. Woo D. Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med 1995; 333: 18–25.

    PubMed  CAS  Google Scholar 

  150. Korsmeyer SJ, Yin XM, Oltvai ZN, Veis-Novack DJ, Linette GP. Reactive oxygen species and the regulation of cell death by the Bc1–2 gene family. Biochim Biophys Acta 1995; 1271: 63–6.

    PubMed  Google Scholar 

  151. Sorenson CM, Rogers SA, Korsmeyer SJ, Hammerman MR. Fulminant metanephric apoptosis and abnormal kidney development in bcl-2-deficient mice. Am J Physiol 1995; 268: F73–81.

    Google Scholar 

  152. Gobe GC, Buttyan R, Wyburn KR, Etheridge MR, Smith PJ. Clusterin expression and apoptosis in tissue remodeling associated with renal regeneration. Kidney Int 1995; 47: 411–20.

    PubMed  CAS  Google Scholar 

  153. Fine LG, Hammerman MR, Abboud HE. Evolving role of growth factors in the renal response to acute and chronic disease (editorial). J Am Soc Nephrol 1992; 2: 1163–70.

    PubMed  CAS  Google Scholar 

  154. O’Shea M, Miller SB, Finkel K, Hammerman MR. Roles of growth hormone and growth factors in the pathogenesis and treatment of kidney disease. Curr Opin Nephrol Hypertens 1993; 2: 67–72.

    PubMed  Google Scholar 

  155. Safirstein R, Zelent AZ, Price PM. Reduced renal prepro-epidermal growth factor mRNA and decreased EGF excretion in ARF. Kidney Int 1989; 36: 810–5.

    PubMed  CAS  Google Scholar 

  156. Humes HD, Cieslinski DA, Coïmbra TM, Messana JM, Galvao C. Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic renal failure. J Clin Invest 1989; 84: 1757–61.

    PubMed  CAS  Google Scholar 

  157. Norman J, Tsau Y-K, Bacay A, Fine LG. Epidermal growth factor enhances recovery from ischaemic acute tubular necrosis in the rat: role of the epidermal growth factor receptor. Clin Science 1990; 78: 445–50.

    CAS  Google Scholar 

  158. Coïmbra TM, Cieslinski DA, Humes HD. Epidermal growth factor accelerates renal repair in mercuric chloride nephrotoxicity. Am J Physiol 1990; 259: F438–43.

    Google Scholar 

  159. Alberti P, Bardella L, Comolli R. Ribosomal protein S6 kinase is activated after folic acid injury and epidermal growth factor administration but not after unilateral nephrectomy in the rat kidney. Nephron 1992; 60: 330–5.

    PubMed  CAS  Google Scholar 

  160. Morin NJ, Laurent G, Nonclerq D, Toubeau G, Heuson-Stiennon J-A, Bergeron MG, Beauchamp D. Epidermal growth factor accelerates renal tissue repair in a model of gentamicin nephrotoxicity in rats. Am J Physiol 1992; 263: F806–11.

    Google Scholar 

  161. Hammerman MR, Miller SB. Therapeutic use of growth factors in renal failure (editorial). J Am Soc Nephrol 1994; 5: 1–11.

    PubMed  CAS  Google Scholar 

  162. Nouwen EJ, Verstrepen WA, De Broe ME. Epidermal growth factor in acute renal failure. Renal Failure 1994; 16: 49–60.

    PubMed  CAS  Google Scholar 

  163. Hammerman MR, Miller SB. The growth hormone insulin-like growth factor axis in kidney revisited (editorial). Am J Physiol 1993; 265: F1–14.

    Google Scholar 

  164. Matejka GL, Jennische E. IGF-I binding and IGF-I mRNA expression in the post-ischemic regenerating rat kidney. Kidney Int 1992; 42: 1113–23.

    PubMed  CAS  Google Scholar 

  165. Kawaida K, Matsumoto K, Shimazu H, Nakamura T. Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci USA 1994; 91: 4357–61.

    PubMed  CAS  Google Scholar 

  166. Miyazawa K, Shimomura T, Naka D, Kitamura N. Proteolytic activation of hepatocyte growth factor in response to tissue injury. J Biol Chem 1994; 269: 8966–70.

    PubMed  CAS  Google Scholar 

  167. Igawa T, Matsumoto K, Kanda S, S ai to Y, Nakamura T. Hepatocyte growth factor may function as a renotropic factor for regeneration in rats with acute renal injury. Am J Physiol 1993; 265: F61–9.

    Google Scholar 

  168. Ishibashi K, Sasaki S, Sakamoto H, Hoshino Y, Nakamura T, Marumo F. Expressions of receptor gene for hepatocyte growth factor in kidney after unilateral nephrectomy and renal injury. Biochem Biophys Res Commun 1992; 187: 1454–9.

    PubMed  CAS  Google Scholar 

  169. Matsumoto K, Tajima H, Hamanoue M, Kohno S, Kinoshita T, Nakamura T. Identification and characterization of “injurin”, an inducer of expression of the gene for hepatocyte growth factor. Proc Natl Acad Sci USA 1992; 89: 3800–4.

    PubMed  CAS  Google Scholar 

  170. Zhang G, Ichimura T, Maier JA, Maciag T, Stevens JL. A role for fibroblast growth factor type-1 in nephrogenic repair. Autocrine expression in rat kidney proximal tubule epithelial cells in vitro and in the regenerating epithelium following nephrotoxic damage by S-C 1,1, 2,2-tetrafluoroethyl)-L-cysteine in vivo. J Biol Chem 1993; 268: 11542–7.

    PubMed  CAS  Google Scholar 

  171. Ghielli M, Verstrepen WA, Nouwen EJ, De Broe ME. Inflammatory cells in renal regeneration. Renal Failure 1996; 18(3): 355–75.

    PubMed  CAS  Google Scholar 

  172. Palier MS, Nath KA, Rosenberg ME. Heme oxygenase is not expressed as a stress protein after renal ischemia. J Lab Clin Med 1993; 122: 341–5.

    Google Scholar 

  173. Flanagan SW, Ryan AJ, Gisolfi CV, Moseley PL. Tissue-specific HSP70 response in animals undergoing heat stress. Am J, Physiol 1995; 268: R28–32.

    Google Scholar 

  174. Moseley PL, Gapen C, Wallen ES, Walter ME, Peterson MW. Thermal stress induces epithelial permeability. Am J Physiol 1994; 267: C425–34.

    Google Scholar 

  175. Hotchkiss R, Nunnally I, Lindquist S, Taulien J, Perdrizet G, Karl I. Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol 1993; 265: R1447–57.

    Google Scholar 

  176. Van Why SK, Mann AS, Thulin G, Zhu XH, Kashgarian M, Siegel NJ. Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat. J Clin Invest 1994; 94: 1518–23.

    PubMed  Google Scholar 

  177. Ohtani H, Wakui H, Komatsuda A, Satoh K, Miura AB, Itoh H, Tashima Y Induction and intracellular localization of 90-kilodalton heat-shock protein in rat kidneys with acute gentamicin nephropathy. Lab Invest 1995; 72: 161–5.

    PubMed  CAS  Google Scholar 

  178. Cowley BD, Gudapaty S. Temporal alterations in regional gene expression after nephrotoxic renal injury. J Lab Clin Med 1995; 125: 187–99.

    PubMed  CAS  Google Scholar 

  179. Martial S, Price SR, Sands JM. Regulation of aldose reductase, sorbitol dehydrogenase, and taurine cotrans-porter mRNA in rat medulla. J Am Soc Nephrol 1995; 5: 1971–8.

    PubMed  CAS  Google Scholar 

  180. Quraishi H, Brown IR. Expression of heat shock protein 90 (hsp90) in neural and nonneural tissues of the control and hyperthermic rabbit. Exp Cell Res 1995; 219: 358–63.

    PubMed  CAS  Google Scholar 

  181. Satoh K, Wakui H, Komatsuda A, Nakamoto Y, Miura AB, Itoh H, Tashima Y Induction and altered localization of 90-kDa heat-shock protein in rat kidneys with cisplatin-induced acute renal failure. Renal Failure 1994; 16: 313–23.

    PubMed  CAS  Google Scholar 

  182. Weiss RA, Madaio MP, Tomaszewski JE, Kelly CJ. T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis. J Exp Med 1994; 180: 2239–50.

    PubMed  CAS  Google Scholar 

  183. Lovis C, Mach F, Donati YR, Bonventre JV, Polla BS. Heat shock proteins and the kidney. Renal Failure 1994; 16: 179–92.

    PubMed  CAS  Google Scholar 

  184. Thomas FT, Tepper MA, Thomas JM, Haisch CE. 15-Deoxyspergualin: a novel immunosuppressive drug with clinical potential. Ann N Y Acad Sci 1993; 685: 175–92.

    PubMed  CAS  Google Scholar 

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Authors
  1. Etienne J. Nouwen
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  2. Robert J. Walker
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  3. George A. Porter
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Editor information

Editors and Affiliations

  1. Division of Nephrology and Hypertension, University of Antwerp, Belgium

    M. E. De Broe  & G. A. Verpooten  & 

  2. Department of Medicine, The Oregon Health Sciences University, Portland, Oregon, 97201, USA

    G. A. Porter

  3. Division of Nephrology, The Oregon Health Sciences University, Portland, Oregon, 97201, USA

    W. M. Bennett

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Nouwen, E.J., Walker, R.J., Porter, G.A. (1998). Cellular mechanisms of nephrotoxicity. In: De Broe, M.E., Porter, G.A., Bennett, W.M., Verpooten, G.A. (eds) Clinical Nephrotoxins. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-9088-4_4

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  • DOI: https://doi.org/10.1007/978-94-015-9088-4_4

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