Skip to main content
SpringerLink
Log in

The effect of a thromboxane A2 synthase inhibitor on the dyslipoproteinemia of an inbred rat strain with spontaneous age-related nephrotic syndrome

  • Original Articles
  • Published:
Aging Clinical and Experimental Research Aims and scope Submit manuscript

Abstract

We have previously shown that the administration of a thromboxane A2 (TXA2) synthase inhibitor (FCE 22178) reduced the progression of glomerular lesions and protein-uria in MNS rats, an inbred strain which develops an age-related nephrotic syndrome. In the present study we investigated the effect of FCE 22178 on the plasma lipoproteins of MNS rats at 28 weeks of age (with mild proteinuria andmoderate dyslipoproteinemia) and at 48 weeks of age (with heavy proteinuria and severe dyslipoproteinemia). Drug treatment reduced proteinuria (by 70% and 36% at 28 and 48 weeks of age, respectively) plasma cholesterol (by 36% and 27% at 28 and 48 weeks of age, respectively) and prevented the decrease of plasma albumin observed in untreated rats (C-MNS) 48 weeks old. In treated rats (T-MNS), the decrease of proteinuria was positively correlated with that of plasma cholesterol. FCE 22178 reduced the elevation in plasma HDL1 (by 17.4%) and HDL2 levels (by 30%), a key feature of nephrotic dyslipoproteinemia in the rat. From 28 to 48 weeks of age plasma apo A-I and apo E increased 217% and 128%, respectively, in C-MNS rats and 191% and 121%, respectively, in T-MNS rats. A significant increase of apo A-I/apo E ratio was found in C-MNS rats from 28 (2.28±0.36) to 48 weeks of age (3.84±0.9) but not in T-MNS rats. FCE 22178 altered the lipid composition of VLDL and HDL2 by reducing the content of cholesteryl esters and increasing that of free cholesterol and phospholipids. These findings suggest that the beneficial effect of FCE 22178 on the dyslipoproteinemia of nephrotic MNS rats is secondary to the amelioration in kidney function and to the reduction of proteinuria produced by this drug. (Aging Clin. Exp. Res. 6; 381–390, 1994)

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

  1. Gray J.E.: Chronic progressive nephrosis in the albino rat. Crit. Reu. Toxicol. 5: 115–144, 1977.

    Article  Google Scholar 

  2. Couser W.G., Stilmant M.M.: Mesangial lesions and focal glomerulosclerosis in the aging rat. Lab. Invest. 33: 491–501, 1975.

    PubMed  CAS  Google Scholar 

  3. Marsh B.J.: Lipoprotein metabolism in experimental nephrosis. J. Lipid Res. 25: 1619–1623, 1984.

    PubMed  CAS  Google Scholar 

  4. Calandra S., Tarugi P.: Influence of age-related nephropathy on plasma lipoproteins of the aging rat. Aging Clin. Exp. Res. 3: 211–218, 1991.

    CAS  Google Scholar 

  5. Bolton W.K., Benton F.R., Maclay J.G., Sturgill B.C.: Spontaneous glomerular sclerosis in aging Sprague- Dawley rats. Am. J. Pathol. 98: 339–356, 1980.

    PubMed  CAS  Google Scholar 

  6. Brandis A., Bianchi G., Reale E., Helmchen U., Kuhn K.: Age-dependent glomerulosclerosis and proteinuria occurring in rats of the Milan Normotensive Strain and not in rats of the Milan Hypertensive Strain. Lab. Invest. 55: 234–243, 1986.

    PubMed  CAS  Google Scholar 

  7. Tarugi P., Nicolini S., Albertazzi L., Calandra S., Salvati P., Ferti C., Patrono C.: Dyslipoproteinemia in an inbred rat strain with spontaneous chronic progressive nephrotic syndrome. J. Lipid Res. 32: 1675–1687, 1991.

    PubMed  CAS  Google Scholar 

  8. Pugliese F., Mené P., Cinotti G.A.: Glomerular prostaglandin and thromboxane synthesis in normotensive and hypertensive rats of the Milan strain before and after development of hypertension. J. Hypertens. 4: S391, 1984

    Google Scholar 

  9. Salvati P., Ferti C., Ferrario R.G., Lamberti E., Duzzi L., Bianchi G., Remuzzi G., Perico N., Benigni A., Braidotti P., Coggi G., Pugliese F., Patrono C.: Role of enhanced glomerular synthesis of thromboxane A2 in progressive kidney disease. Kidney Int. 38: 447–458, 1990.

    Article  PubMed  CAS  Google Scholar 

  10. Lianos E.A., Andres A.A., Dunn M.J.: Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. J. Clin. Invest. 72: 1439–1448, 1983.

    Article  PubMed  CAS  Google Scholar 

  11. Macconi D., Benigni A., Morigi M., Ubiali A., Orisio S., Livio M., Perico N., Bertani T., Remuzzi G., Patrono C.: Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials. J. Lab. Clin. Med. 113: 549–560, 1989.

    PubMed  CAS  Google Scholar 

  12. Remuzzi G., Imberti L., Rossini M., Morelli C., Carminati C., Cattaneo G.M., Bertani T.: Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis. J. Clin. Invest. 75: 94–101, 1985.

    Article  PubMed  CAS  Google Scholar 

  13. Patrono C., Ciabattoni G., Remuzzi G., Gotti E., Bombardieri S., Di Munno O., Tartarelli G., Cinotti G.A., Simonetti B.M., Pierucci A.: Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus. J. Clin. Invest. 76: 1011–1018, 1985.

    Article  PubMed  CAS  Google Scholar 

  14. Purkeson M.L., Joist J.H., Yates J., Klahr S.: Inhibition of thromboxane synthesis ameliorates the progressive kidney disease of rats with subtotal renal ablation. Proc. Natl. Acad. Sci. USA 82: 193–197, 1985.

    Article  Google Scholar 

  15. Craven P.A., Melhem M.F., De Rubertis F.R.: Thromboxane in the pathogenesis of glomerular injury in diabetes. Kidney Int. 42: 937–946, 1992.

    Article  PubMed  CAS  Google Scholar 

  16. Niwa T., Maeda K., Shibata M., Yamada K.: Clinical effects of selective thromboxane A2 synthetase inhibitor in patients with nephrotic syndrome. Clin. Nephrol. 30: 276–281, 1988.

    PubMed  CAS  Google Scholar 

  17. Pierucci A., Simonetti B.M., Pecci G., Mavrikakis G., Feriozzi S., Cinotti G.A., Patrignani P., Ciabattoni G., Patrono C.: Improvement of renal function with selective thromboxane antagonism in lupus nephritis. N. Engl. J. Med. 320: 421–425, 1989.

    Article  PubMed  CAS  Google Scholar 

  18. Bianchi G., Ferrari P., Barber B.R.: Experimental and genetic model of hypertension. In: de Jong W. (Ed.), Handbook of Hypertension, Vol 4. Elsevier Publisher, Amsterdam, 1984, p. 234.

    Google Scholar 

  19. Cozzi P., Branzoli V., Carganico G., Pillan A., Lovisolo P.P., Cangiano G., Chiari A.: N-imidazolyl derivatives of the naphthalene and chroman rings as selective inhibitors of thromboxane A2 (TXA2) synthetase. Joint Meeting in Medicinal Chemistry T3, 1985 (Abstract).

  20. Hermier D., Forgez P., Chapman M.J.: A density gradient study of lipoprotein and apolipoprotein distribution in the chicken, Gallus domesticus. Biochim. Biophys. Acta 836: 105–118, 1985.

    Article  PubMed  CAS  Google Scholar 

  21. Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J.: Protein measurement with the Folin-Phenol reagent. J. Biol. Chem. 193: 265–275, 1951.

    PubMed  CAS  Google Scholar 

  22. Calandra S., Tarugi P., Ghisellini M., Gherardi E.: Plasma and urine lipoproteins during the development of nephrotic syndrome induced in the rat by adriamycin. Exp. Mol. Pathol. 39: 282–299, 1983.

    Article  PubMed  CAS  Google Scholar 

  23. Folch J., Lees M., Sloane Stanley G.H.: A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226: 497–509, 1957.

    PubMed  CAS  Google Scholar 

  24. Gherardi E., Vecchia L., Calandra S.: Experimental nephrotic syndrome in the rat induced by puromycin aminonucleoside. Plasma and urinary lipoproteins. Exp. Mol. Pathol. 32: 128–142, 1980.

    Article  CAS  Google Scholar 

  25. Laemmli U.K.: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685, 1970.

    Article  PubMed  CAS  Google Scholar 

  26. Calandra S., Tarugi P., Ghisellini M.: Separation of the isoprotein forms of apoprotein A-I of rat, rabbit and human HDL by combined isoelectrofocusing and SDS-polyacrylamide gel electrophoresis. Atherosclerosis 50: 209–221, 1984.

    Article  PubMed  CAS  Google Scholar 

  27. Marsh B.M., Sparks C.E.: Lipoproteins in experimental nephrosis: plasma levels and composition. Metabolism 28: 1040–1045, 1979.

    Article  PubMed  CAS  Google Scholar 

  28. Gherardi E., Calandra S.: Plasma and urinary lipids and lipoproteins during the development of nephrotic syndrome induced in the rat by puromycin aminonucleoside. Biochim. Biophys. Acta 710: 188–196, 1982.

    Article  PubMed  CAS  Google Scholar 

  29. Grond J., van Goor H., Elema J.D.: Histochemical analysis of focal and segmental hyalinosis and sclerosis lesions in various rat models of experimental nephrotic syndrome. Kidney Int. 29: 945–946, 1986.

    Google Scholar 

  30. Diamond J.R., Karnovsky M.J.: Exacerbation of chronic aminonucleoside nephrosis by dietary cholesterol supplementation. Kidney Int. 32: 671–677, 1987.

    Article  PubMed  CAS  Google Scholar 

  31. Diamond J.R., Karnovsky M.J.: Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int. 33: 917–924, 1988.

    Article  PubMed  CAS  Google Scholar 

  32. Diamond J.R., Pesek I., McCarter M.D., Karnovsky M.J.: Altered functional characteristics of rat macrophages during nephrosis. Am. J. Pathol. 135: 711–718, 1989.

    PubMed  CAS  Google Scholar 

  33. Diamond R.J.: Effects of dietary interventions on glomerular pathophysiology. Am. J. Physiol. 258: F1–F8, 1990.

    PubMed  CAS  Google Scholar 

  34. Diamond J.R., Hanchak N.A., McCarter M.D., Karnovsky M.J.: Cholestyramine resin ameliorates chronic aminonucleoside nephrosis. Am. J. Clin. Nutr. 51: 606–611, 1990.

    PubMed  CAS  Google Scholar 

  35. Kasiske B.L., O’Donnell M.P., Garvis W.J., Keane W.F.: Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ. Res. 62: 367–374, 1988.

    Article  PubMed  CAS  Google Scholar 

  36. Diamond J.R.: Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis. Kidney Int. 31: S29–S34, 1991.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of General Pathology, University of Modena School of Medicine, Via Campi 287, 41100, Modena, Italy

    P. Tarugi Ph.D., S. Nicolini, L. Albertazzi, L. Marchi & S. Calandra

  2. Farmitalia Carlo-Erba Research Laboratories, Nerviano, Milano, Italy

    P. Salvati

Authors
  1. P. Tarugi Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Nicolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Albertazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Marchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Calandra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. Salvati
    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

Tarugi, P., Nicolini, S., Albertazzi, L. et al. The effect of a thromboxane A2 synthase inhibitor on the dyslipoproteinemia of an inbred rat strain with spontaneous age-related nephrotic syndrome. Aging Clin Exp Res 6, 381–390 (1994). https://doi.org/10.1007/BF03324269

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03324269

En]Keywords

Search

Navigation