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Aminoglycoside Antibiotics Inhibit the Phosphatidylinositol Cascade in Renal Proximal Tubular Cells: Possible Role in Toxicity

  • Chapter
Nephrotoxicity

Abstract

A growing body of evidence supports the conclusion that aminoglycoside antibiotics (AG) interact with phosphoinositides. For example AG have been shown to bind to phosphoinositides in model membranes (1–5) by a mechanism best explained by an electrostatic interaction (3,5). The strong avidity of these drugs for phosphatidylinositol-4,5-bisphosphate (PIP2) (1,5,6) has led to the hypothesis that PIP2 serves as the biological receptor for these agents (6–8). AG have been shown to induce a phosphatidylinositol (PI)-enriched phospholipidosis in rat renal cortex (9,10) and in cells grown in culture (11,12), a phenomenon which may be related to the observation that AG have the capacity to inhibit a PI-specific phospholipase C (13–15). Moreover, neomycin has been shown to block the hydrolysis of PIP2 and the generation of inositol trisphosphate (IP3) in response to agonist stimulation in vitro (16,17) and to depress the synthesis and turnover of (32P]PIP2 in vitro and in vivo (1,18,19) . These observations indicate that AG have the potential to perturb the PI cascade, which serves as the transmembrane signal transducing mechanism for a number of agonists (20). Inhibition of the PI cascade by AG might cause profound derangements in the regulation of a number of intracellular processes and thereby contribute to the toxicity of these agents.

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References

  1. J. Schacht, N.D. Weiner and S. Lodhi, Interaction of aminocyclitol antibiotics with polyphosphoinositides in mammalian tissues and artificial membranes, In: Cyclitols and Phosphoinositides, W.W. Wells and F. Eisenberg, ed., Academic Press, New York (1978) .

    Google Scholar 

  2. R. Brasseur, G. Laurent, J.M. Ruysschaert and P. Tulkens, Interactions of aminoglycoside antibiotics with negatively charged lipid layers, Biochem. Pharmacol. 33:629 (1984).

    Article  PubMed  CAS  Google Scholar 

  3. L. Chung, G. Kaloyanides, R. McDaniel, A. McLaughlin and S. McLaughlin, Tnteraction of gentamicin and spermine with bilayer membranes containing negatively charged phospholipids, Biochemistry 24:442 (1985).

    Article  PubMed  CAS  Google Scholar 

  4. L. Ramsammy and G.J. Kaloyanides, Effect of gentamicin on the transition temperature and permeability to glycerol of phosphatidyl-inositol-containing liposomes, Biochem. Pharmacol. 36:1179 (1987).

    Article  PubMed  CAS  Google Scholar 

  5. S. Au, N.D. Weiner and J. Schacht, Aminoglycoside antibiotics prefer-entially increase the permeability in phosphoinositide-containing membranes: a study with carboxyfluorescein in liposomes. Biochim. Biophvs. Acta 902:80 (1987).

    Article  CAS  Google Scholar 

  6. J. Schacht, Isolation of an aminoglycoside receptor from guinea pig inner ear tissues and kidney, Arch. Otorhinolarvngol. 224:129 (1979).

    Article  CAS  Google Scholar 

  7. J. Schacht, Molecular mechanisms of drug-induced hearing loss, Hearing Res. 22:297 (1986) .

    Article  CAS  Google Scholar 

  8. M. Sastrasinh, T.C. Rnauss, J.M. Weinberg and H.D.Humes, Identification of the aminoglycoside receptor of renal brush border membrane, J. Pharmacol. Exp. Ther. 222:350 (1982).

    PubMed  CAS  Google Scholar 

  9. S. Peldman, M. Wang and G.J. Kaloyanides, Aminoglycosides induce a phospholipidosis in the renal cortex of the rat: An early manifestation of nephrotoxicity, J. Pharmacol. Exp. Ther. 220:514 (1982).

    Google Scholar 

  10. C. Josepovitz, T. Farruggella, R. Levins, B. Lane and G.J. Kaloyanides, Effect of netilmicin on the phospholipid composition of subcellular fractions of rat renal cortex. J. Pharmacol. Exp. Ther. 235:810 (1985) .

    PubMed  CAS  Google Scholar 

  11. D. W. Schwertz, J. I. Greisberg and M.A. Venkatachalam, Gentamicin-induced alterations in pig kidney epithelial (LLC-PK1) cells in culture, J. Pharmacol. Exp. Ther. 236:254 (1986).

    PubMed  CAS  Google Scholar 

  12. C. Josepovitz, L. Ramsammy, B. Lane and G.J. Kaloyanides, Gentamicin inhibits degradation and stimulates synthesis of phosphatidylinositol in primary culture of rabbit proximal tubular cells. Kidney Int. 31:369 (1987) .

    Google Scholar 

  13. J.J. Lipsky and P.S. Lietman, Aminoglycoside inhibition of a renal phosphatidylinositol phospholipase C, J. Pharmacol. Exp. Ther. 220:287 (1982).

    PubMed  CAS  Google Scholar 

  14. K.Y. Gostetler and L.B. Hall, Inhibition of kidney lysosomal phospholipases A and C by aminoglycoside antibiotics: Possible mechanism of aminoglycoside toxicity. Proc. Natl. Acad. Sci. USA 79:1663 (1982).

    Article  Google Scholar 

  15. D.W. Schwertz, J.I. Ereisberg and M.A. Ventkatachalam, Effects of aminoglycosides on proximal tubule brush border membrane phosphatidyl-inositol-specific phospholipase-C, J. Pharmacol. Exp. Ther. 231:48 (1984).

    PubMed  CAS  Google Scholar 

  16. H. Streb, J.P. Heslop, R.F. Irvine, I. Schulz and M.J. Berridge, Relationship between secretagogue-induced Ca++ release and inositol polyphosphate production in permeabilized pancreatic acinar cells. J. Biol. Chem. 260:7309 (1985) .

    PubMed  CAS  Google Scholar 

  17. W. Siess and E.G. Lapetine, Neomycin inhibits inositol phosphate formation in human platelets stimulated by thrombin but not other agonists, FEBS 267:53 (1986) .

    Article  Google Scholar 

  18. P. Marche, S. Komtouzov and A. Girard, Impairment of membrane phosphoinositide metabolism by aminoglycoside antibiotics: streptomycin, amikacin, kanamycin, dibekacin, gentamicin and neomycin, J. Pharmacol. Exp. Ther. 227:415 (1983) .

    PubMed  CAS  Google Scholar 

  19. P. Marche, B. Olier, A. Girard, J.-P. Fillastre and J.-P. Morin, Aminoglycoside-induced alterations of phosphoinositide metabolism 31:59 (1987) .

    CAS  Google Scholar 

  20. M.J. Berridge, Inositol trisphosphate and dicylglycerol: two interacting second messengers, Ann. Review Biochem. 56:159 (1987).

    Article  CAS  Google Scholar 

  21. M. Taub, Growth of primary and established kidney cell cultures in serum-free media, In: Methods for Serum-Free Culture of Epithelial and Fibroblastic Cells, Alan R. Liss, Inc., New York (1984).

    Google Scholar 

  22. C.P. Downes and R.B. Michell, The polyphosphoinositide phosphodiesterase of erythrocyte membranes, Biochem. J. 198:133 (1981).

    PubMed  CAS  Google Scholar 

  23. R. Minakuchi, Y. Takai, B. Yu and Y. Nishizuka, Widespread occurrence of calcium-activated, phospholipid dependent protein kinase in mammalian tissues, J. Biochem. 89:165 (1981).

    Google Scholar 

  24. R.V. Farese, P. Bidot-Lopez, A. Sabir, and J.S. Smith, Parathyroid hormone acutely increases polyphosphoinositides of the rabbit kidney cortex by a cycloheximide-sensitive process. J. Clin. Invest. 65:1523 (1980) .

    Article  PubMed  CAS  Google Scholar 

  25. E.A. Hruska, D. Moskowitz, P. Esbrit, R. Civitelli, S. Westbrook and M. Huskey, Stimulation of inositol trisphosphate and diacylglycerol production in renal tubular cells by parathyroid hormone, J. Clin. Invest. 79:230 (1987) .

    Article  PubMed  CAS  Google Scholar 

  26. H. Rasmussen, I. Rojima, W. Apfeldorp and P. Barrett, Cellular mechanism of hormone action in the kidney: messenger function of calcium and cyclic AMP, Kidney Int. 29:90 (1986) .

    Article  PubMed  CAS  Google Scholar 

  27. E. Pastoriza-Munoz, R.E. Colindres, W.E. Lassiter and C. Lechene, Effect of parathyroid hormone on phosphate reabsorption in the rat distal convolntion., Am. J. Physiol. 235:F321 (1978).

    Google Scholar 

  28. L. Soberon, R.L. Bowman, E. Pastoriza-Munoz and G.J. Kaloyanides, Comparative nephrotoxicities of gentamicin, tobramysinpp gentamicin, netilmicin and tobramysin in the rat, J. Pharmacol. Exp. Thr. 210:324 (1979).

    Google Scholar 

  29. L. Ramsammy, G.-Y. Ling, C. Josepovitz, R. Levine and G.J. Kaloyanides, Effect of gentamicin on lipid peroxidation in rat renal cortex, Biochem. Pharmacol. 34:3895 (1985).

    Article  PubMed  CAS  Google Scholar 

  30. G. Wirthensohn and W. G. Guder, stimulation of phospholipid turnover by angiotensin II and phenylephrine in proximal convoluted tubules microdissected from mouse nephron, Pflugers Arch. 404:94 (1985) .

    Article  PubMed  CAS  Google Scholar 

  31. J.A. Shayman and A.R. Morrison, Bradykinin-induced changes in phosphatidylinositol turnover in cultured rabbit papillary collecting tubules, J. Clin. Invest. 76:978 (1985).

    Article  PubMed  CAS  Google Scholar 

  32. D.A. Troyer, D.W. Schwertz, J.I. Rreisberg and M.A. Venkatachalam, Inositol phospholipid metabolism in the kidney, Ann. Review Physiol. 48:51 (1986) .

    Article  CAS  Google Scholar 

  33. H. Rasmussen, The calcium messenger system. New Engl, J. Med. 314:1164 (1986) .

    Article  CAS  Google Scholar 

  34. Y. Nishizuka, Studies and perspectives of protein kinase C, Science 233:305 (1986).

    Article  PubMed  CAS  Google Scholar 

  35. W.H. Moolenar, Effects of growth factors on intracellular pH regulation, Ann. Rev. Physiol. 48:363 (1986).

    Article  Google Scholar 

  36. A.M. Jetten, B.R. Ganong, G.R. Vandenbark, I.E. Shirley and R.M. Bell, Role of protein kinase C in diacylglycerol-mediated induction of ornithine decarboxylase and reduction of epidermal growth factor binding. Proc. Natl. Acad. Sci. USA 82:1941 (1985).

    Article  PubMed  CAS  Google Scholar 

  37. M.A. Grillo, Metabolism and function of polyamines, Int. J. Biochem. 17:943 (1985) .

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department, Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, 11794, USA

    George J. Kaloyanides & Leslie S. Ramsammy

  2. Veterans Administration Medical Center, Northport, NY, 11768, USA

    George J. Kaloyanides & Leslie S. Ramsammy

Authors
  1. George J. Kaloyanides
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  2. Leslie S. Ramsammy
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Editor information

Editors and Affiliations

  1. The Robens Institute of Industrial and Environmental Health and Safety, University of Surrey, Guildford, Surrey, UK

    P. H. Bach

  2. ICI Central Toxicology Laboratory, Macclesfield, Cheshire, UK

    E. A. Lock

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© 1989 Springer Science+Business Media New York

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Kaloyanides, G.J., Ramsammy, L.S. (1989). Aminoglycoside Antibiotics Inhibit the Phosphatidylinositol Cascade in Renal Proximal Tubular Cells: Possible Role in Toxicity. In: Bach, P.H., Lock, E.A. (eds) Nephrotoxicity. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-2040-2_28

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  • DOI: https://doi.org/10.1007/978-1-4757-2040-2_28

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4757-2042-6

  • Online ISBN: 978-1-4757-2040-2

  • eBook Packages: Springer Book Archive

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