Skip to main content
SpringerLink
Log in

The role of lysosomes in hyaline droplet nephropathy induced by a variety of pharmacological agents in the male rat

  • Review
  • Published:
The Histochemical Journal Aims and scope Submit manuscript

Summary

The male rat is prone to hyaline droplet formation in renal proximal tubular cells. Several unrelated pharmaceutical agents exacerbate the formation and accumulation of these droplets. Where the loading of the proximal tubular cells is marked it gives rise to increased cell turnover and a hyaline droplet nephropathy develops. Cytochemical procedures, have confirmed that this accumulation of hyaline droplets represents an increase in the size and number of secondary lysosomes involved in protein uptake and metabolism. This predisposition of the male rat to develop hyaline droplet nephropathy relates to (1) the large amounts of the low-molecular-weight protein α2U globulin in the glomerular filtrate, (2) the resistance of the globulin to proteolysis, and (3) the low protease activity in the proximal tubule lysosomes. The current data would suggest that the pharmacological agents, which cause the nephropathy, exert their effect by reducing the proteolytic breakdown of α2U globulin in the proximal tubule lysosomes. This results in the overloading of a system which is already operating near maximal load. Female rats, and all other species excrete only small amounts of α2U globulin or similar proteins, which are more easily hydrolized. Thus it is argued that the type of hyaline droplet nephropathy induced by these pharmacological agents is unique to the male rat and of little relevance to man.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alden, C. L. (1985) Species, sex, and tissue specificity in toxicologic and proliferative responses.Toxicol. Pathol. 13, 135–40.

    Google Scholar 

  • Alden, C. L. (1986) A review of unique male rat hydrocarbon nephropathy.Toxicol. Pathol. 14, 109–11.

    Google Scholar 

  • Alden, C. L., Kanerva, R. L., Ridder, G. &Stone, L. C. (1984) The pathogenesis of the nephrotoxicity of volatile hydrocarbons in the male rat. InRenal Effects of Petroleum Hydrocarbons. Advances in Modern Environmental Toxicology (edited byMehlman, M. A., Hemstreet, J. J., Thorpe, N. K. &Weaver, N. K.) Vol. VII, pp. 107–20. Princeton, New Jersey: Princeton Scientific Publishers Inc.

    Google Scholar 

  • Blackett, N. M. &Parry, D. M. (1977) A simplified method of ‘hypothetical grain’ analysis of electron microscope autoradiographs.J. Histochem. Cytochem. 25, 206–14.

    Google Scholar 

  • Charbonneau, M., Lock, E. A., Strasser, J., Cox, M. G., Turner, M. J. &Bus, J. S. (1987) 2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats.Toxicol. Appl. Pharmacol. 91, 171–81.

    Google Scholar 

  • Charbonneau, M., Strasser, J., Borghoff, S. J. &Swenberg, J. A. (1988)In vitro hydrolysis of [14C]-α2U-globulin (α2U) isolated from male rat kidney.Toxicologist 8, 135.

    Google Scholar 

  • Christensen, E. I. (1976) Rapid uptake and digestion in proximal tubule lysosomes.Kidney Int. 10, 301–10.

    Google Scholar 

  • Christensen, E. I. &Maunsbach, A. B. (1974) Intralysosomal digestion of lysozyme in renal proximal tubule cells.Kidney Int. 6, 396–407.

    Google Scholar 

  • Christensen, E. I. &Maunsbach, A. B. (1980) Digestion of proteins in lysosomes of proximal tubule cells. InFunctional Ultrastructure of the Kidney (edited byMaunsbach, A. B., Olson, T. S. &Christensen, E. I.) pp. 341–59. London, New York: Academic Press.

    Google Scholar 

  • Evans, G. O., Goodwin, D. A., Parsons, C. E. &Read, N. G. (1988) The effects of Levamisole on urinary enzyme measurements and proximal tubule cell inclusions in male rats.Br. J. Exp. Path. 69, 301–8.

    Google Scholar 

  • Feigelson, P. &Kurtz, D. T. (1978) Hormonal modulation of specific messenger RNA species in normal and neoplastic rat liver.Adv. Enzymol. 47, 275–312.

    Google Scholar 

  • Halder, C. A., Warne, T. M. &Hatoum, N. S. (1984) Renal toxicity of gasoline and related petroleum naphthas in male rats. InRenal Effects of Petroleum Hydrocarbons. Advances in Modern Environmental Toxicology (edited byMehlman, M. A., Hemstreet, J. J., Thorpe, N. K. &Weaver, N. K.) Vol. VII, pp. 73–88. Princeton, New Jersey: Princeton Scientific Publishers Inc.

    Google Scholar 

  • Jedrzejewski, K. &Kugler, P. (1982) Peptidases in the kidney and urine of rats after castration.Histochemistry 74, 63–84.

    Google Scholar 

  • Kanerva, R. L., Ridder, G. M., Stone, L. C. &Alden, C. L. (1987) Characterization of spontaneous and decalin-induced hyaline droplets in kidneys of adult male rats.Food Chem. Toxicol. 14, 63–82.

    Google Scholar 

  • Kitchen, D. N. (1984) Neoplastic renal effects of unleaded gasoline in Fischer 344 rats. InRenal Effects of Petroleum Hydrocarbons. Advances in Modern Environmental Toxicology (edited byMehlman, M.A., Hemstreet, J.J., Thorpe, N.K. &Weaver, N.K.) Vol VII, pp. 65–71. Princeton, New Jersey: Princeton Scientific Publishers Inc.

    Google Scholar 

  • Kugler, P. (1982) Quantitative histochemistry of the lysosomal dipeptidyl amino-peptidase II in the proximal tubule of the rat kidney.Histochemistry 76, 557–66.

    Google Scholar 

  • Kugler, P. &Vornberger, G. (1986) Renal cathepsin-B activities in rats after castration and treatment with sex hormones.Histochemistry 85, 157–61.

    Google Scholar 

  • Kurtz, D. T., Sippel, A. E. &Peigelson, P. (1976) Effect of thyroid hormone on the level of the hepatic mRNA for α2U globulin.Biochemistry 15, 1031–6.

    Google Scholar 

  • Kurtz, D. T., Chan, K. M. &Feigelson, P. (1978) Glucocorticoid induction of hepatic α2U-globulin synthesis and messenger RNA level in castrated male ratsin vivo.J. Biol. Chem. 253, 7886–90.

    Google Scholar 

  • Laperche, Y., Lynch, K. R., Dolan, K. P. &Feigelson, P. (1983) Fissue-specific control of α2U globulin gene expression: constitutive synthesis in the submaxillary gland.Cell 32, 453–60.

    Google Scholar 

  • Lehman-Mckeeman, L. D., Rivera-Torres, M. I. &Caudill, D. (1990) Lysosomal degradation of α2U-globulin and α2U-globulin-xenobiotic conjugates.Toxicol. Appl. Pharmacol. 103, 539–48.

    Google Scholar 

  • Lynch, K. R., Dolan, K. P., Nakhasi, H. L., Unterman, R. &Feigelson, P. (1982) The role of growth hormone in α2U globulin synthesis: a re-examination.Cell 28, 185–9.

    Google Scholar 

  • Maunsbach, A. B. (1966) Electron microscopic observations of cytoplasmic bodies with crystalline patterns in rat kidney proximal tubule cells.J. Ultrastruct. Res. 14, 167–89.

    Google Scholar 

  • Murty, C. V. R., Olson, M. J., Garg, B. D. &Roy, A. K. (1988) Hydrocarbon-induced hyaline droplet nephropathy in male rats during senescence.Toxicol. Appl. Pharmacol. 96, 380–92.

    Google Scholar 

  • National Toxicology Program (1986) Carcinogenesis bioassay of 1,4-dichlorobenzene in F344/N rats and B6 C3F1 mice. (Gavage Study). InNTP Technical Report No. 319. Research Triangle Park, N.C.: National Toxicology Program.

    Google Scholar 

  • Neuhaus, O. W. (1986) Renal reabsorption of low molecular weight proteins in adult male rats: α2U-globulin.Proc. Soc. Exp. Biol. Med. 182, 531–9.

    Google Scholar 

  • Neuhaus, O. W., Flory, W., Biswas, N., &Hollerman, C. E. (1981) Urinary excretion of α2U-globulin and albumin by adult male rats following treatment with nephrotoxic agents.Nephron 28, 133–40.

    Google Scholar 

  • Pervaiz, S. &Brew, K. (1987) Homology and structurefunction correlations between α1-acid glycoprotein and serum retinol-binding protein and its relatives.FASEB J. 1, 209–14.

    Google Scholar 

  • Pevsner, J., Reed, R. R., Feinstein, P. G. &Snyder, S. H. (1988) Molecular cloning of odorant-binding protein: member of a ligand carrier family.Science 241, 336–9.

    Google Scholar 

  • Pitha, J. V., Hemstreet, G. P., III, Asal, N. R., Petrone, R. L., Trump, B. F. &Silva, F. G. (1987) Occupational exposure and renal histopathology.Toxicol. Ind. Health 3, 491–506.

    Google Scholar 

  • Read, N. G., Astbury, P. J., Morgan, R. J. I., Parsons, D. N. &Port, C. J. (1988) Induction and exacerbation of hyaline droplet formation in the proximal tubular cells of the kidneys from male rats receiving a variety of pharmacological agents.Toxicology 52, 81–101.

    Google Scholar 

  • Roy, A. K. (1973) Androgen-dependent synthesis of α2U-globulin in the rat: role of the pituitary gland.J. Endocrinol. 56, 295–301.

    Google Scholar 

  • Roy, A. K. (1977) Early events in the steroidal regulation of α2U globulin in rat liver.Eur. J. Biochem. 73, 537–43.

    Google Scholar 

  • Roy, A. K. &Neuhaus, O. W. (1966) Proof of the hepatic synthesis of a sex-dependent protein in the rat.Biochim. Biophys. Acta 127, 82–7.

    Google Scholar 

  • Roy, A. K. &Raber, D. L. (1972) Immunofluorescent localization of α2U-globulin in the hepatic and renal tissue of rat.J. Histochem. Cytochem. 20, 89–96.

    Google Scholar 

  • Roy, A. K., Mcminn, D. M. &Biswas, N. M. (1975) Estrogenic inhibition of the hepatic synthesis of alpha 2U globulin in the rat.Endocrinology 97, 1501–8.

    Google Scholar 

  • Roy, A. K., Schiop, M. J. &Dowbenko, D. J. (1976) Regulation of the hepatic synthesis of α2U globulin and its corresponding messenger RNA in maturing male rats.Febs. Lett. 70, 137–40.

    Google Scholar 

  • Roy, A. K., Chatterjee, B., Prasad, M. S. K. &Unaki, N. J. (1980) Role of insulin in the regulation of the hepatic messenger RNA for α2U-globulin in diabetic rats.J. Biol. Chem. 255, 11614–8.

    Google Scholar 

  • Stonard, M. D., Phillips, P. G. N., Foster, J. R., Simpson, M. G. &Lock, E. A. (1986) α2U-globulin Measurement in rat kidney following administration of 2,2,4-trimethylpentane.Toxicology 41, 161–8.

    Google Scholar 

  • Swenberg, J. A., Short, B., Borghoff, S., Strasser, J. &Charbonneau, M. (1989) The comparative pathobiology of α2U-globulin nephropathy.Toxicol. Appl. Pharmacol. 97, 35–46.

    Google Scholar 

  • Vandoren, G., Mertens, B., Heyns, W., Van Baelen, H., Rombauts, W. &Verhoeven, G. (1983) Different forms of α2U-globulin in male and female rat urine.Eur. J. Biochem. 134, 175–81.

    Google Scholar 

  • Viau, C., Bernard, A., Gueret, F., Maldague, P., Gengoux, P. &Lauwerys, R. (1986) Isoparaffinic solvent-induced nephrotoxicity in the rat.Toxicology 38, 227–40.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Drug Safety Evaluation, The Wellcome Research Laboratories, The Wellcome Foundation Ltd., Langley Court, BR3 3BS, Beckenham, Kent, UK

    Nicholas G. Read

Authors
  1. Nicholas G. Read
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Read, N.G. The role of lysosomes in hyaline droplet nephropathy induced by a variety of pharmacological agents in the male rat. Histochem J 23, 436–443 (1991). https://doi.org/10.1007/BF01041373

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01041373

Keywords

Search

Navigation