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Pakistan Journal of Biological Sciences

Year: 2005 | Volume: 8 | Issue: 12 | Page No.: 1712-1719
DOI: 10.3923/pjbs.2005.1712.1719
Structural Effects of Vitamin E on Proximal Tubule and Interstitium in a Rat Model of Cyclosporin A Nephrotoxicity
Yesim Hulya Uz and Muberra Uygun

Abstract: The aim of this study was to investigate whether the antioxidant vitamin E provided morphological protection in the nephrotoxicity caused by Cyclosporin A (CsA). Twenty-five Sprague-Dawley male rats were divided into five groups, each consisting of five rats. One of them was the control group and four of them were the experiment group. CsA (5 mg kg-1 day-1) to the Group II, III and V, CsA plus vitamin E (5 mg kg-1 day-1) to the Group IV were administered intraperitoneally (i.p.) for 8 weeks. The kidney specimens of the Group I, II and IV were taken at the end of the 8th week. The kidney specimens of the Group III were taken at the end of 14th week after they had been kept for reversibility for 6 weeks. As for t he kidney specimens of the Group V, they were administered vitamin E ( 5 mg kg-1 day-1) for 6 weeks after the administration of CsA (5 mg kg-1 day-1) for 8 weeks and then were taken at the end of the 14th week. All of these kidney specimens were processed for light and electron microscopical examination. In the Group II, infiltration foci and increase of interstitial connective tissue were observed at the surrounding of vessels, especially in the corticomedullary region. The most obvious changes were encountered in the proximal tubules. These changes were seen as degeneration and regeneration. While the degeneration was seen as the thickening of basement membrane, loss of brush border, vacuolization, dilation of the smooth endoplasmic reticulum, increase in lysosomes in number and size, the proliferation of some of the scattered epithelial cells of the tubules formed the regeneration areas by causing the appearance of new tubules. No obvious regression was seen in the Group III and more or less the same changes as in the Group II were observed. As vitamin E inhibited the oxidative damage of CsA, the least damage occurred in the Group IV. Because of the release of CsA accumulated in tissues later giving it into the organism, more damage was observed in the Group V compared to Group IV. Therefore, using CsA and vitamin E simultaneously may keep the nephrotoxicity caused by CsA at a minimal level.

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How to cite this article
Yesim Hulya Uz and Muberra Uygun, 2005. Structural Effects of Vitamin E on Proximal Tubule and Interstitium in a Rat Model of Cyclosporin A Nephrotoxicity. Pakistan Journal of Biological Sciences, 8: 1712-1719.

Keywords: vitamin E, Cylosporin A, kidney, proximal tubule and interstitium

REFERENCES

  • Mohamadin, A.M., H.A. El-Beshbishy and M.A. El-Mahdy, 2005. Green tea extract attenuates cyclosporine A-induced oxidative stress in rats. Pharmacol. Res., 51: 51-57.
    CrossRef    PubMed    Direct Link    


  • Borel, J.F., C. Feurer, H.U. Gubler and H. Stahlein, 1976. Biological effects of cyclosporin A: A new antilymphocytic agent. Agents Act., 6: 468-475.
    PubMed    


  • Kahan, B.D., 1989. Drug therapy. N. Engl. J. Med., 321: 1725-1738.


  • Cid, T.P., J.R.C. Garcia, F.C. Alvarez and G. de Arriba, 2003. Antioxidant nutrients protect against cyclosporine a nephrotoxicity. Toxicology, 189: 99-111.
    CrossRef    PubMed    Direct Link    


  • Bennet, W.M., 1986. Comparison of cyclosporine nephrotoxicity with aminoglygoside nephrotoxicity. Clin. Nephrol., 25: 126-129.
    PubMed    


  • Schrier, R.W. and C.W. Gottschalk, 1993. Outcome and complications of renal transplantation. Dis. Kidney, 3: 2926-2929.


  • Palastine, A.G., R.B. Nussenblatt and C.C. Chan, 1984. Side effect of systemic cyclosporine in patients not undergoing transplantation. Am. J. Med., 77: 652-656.
    PubMed    


  • Thiel, G., 1986. Experimental cyclosporine a nephrotoxicity a summary of the international workshop (Basle, April 24-26, 1985). Clin. Nephrol., 25: 205-210.


  • Calne, R.Y., D.J.G. White, S. Thiru, D.B. Evans and P. McMaster et al., 1978. Cyclosporine a in patients receving renal allografts from cadaver donors. Lancet, 2: 1323-1327.
    PubMed    


  • Mason, J., 1990. Renal side-effects of cyclosporin A. Br. J. Dermatol., 122: 71-77.


  • Dieperink, H., H. Starklint, E. Kemp and P.P. Leyssac, 1988. Comparative pathophysiology and histopathology of cyclosporine nephrotoxicity. Transplant. Proc., 20: 785-791.
    PubMed    


  • Jackson, N.M., C.H. Hsu, G.E. Visscher, M.A. Venkatachalam and H.D. Humes, 1987. Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity. J. Pharmacol. Exp. Ther., 242: 749-756.
    Direct Link    


  • Olbricht, C.J., H.J. Grone, C. Bossaller, E. Gutjahr and R.F. Hertel, 1990. Alterations in proteolytic enzymes of the proximal tubule in a rat model of cyclosporine nephrotoxicity. Transplantation, 50: 378-381.


  • Whiting, P.H., J.G. Simpson, R.J.L. Davidson and A.W. Thomson, 1983. Pathological changes in rats receiving cyclosporin A at immunotherapeutic dosage for 7 weeks. Br. J. Exp. Pathol., 64: 437-444.
    Direct Link    


  • Verani, R., 1986. Cyclosporine nephrotoxicity in the Fischer rat. Clin. Nephrol., 25: 9-13.


  • Dieperink, H., P.P. Leyssac, E. Kemp, H. Starklint, N.E. Frandsen et al., 1987. Nephrotoxicity of cyclosporin a in humans effects on glomerular filtration and tubular reabsorption rates. Eur. J. Clin. Invest., 17: 493-496.


  • Pfaller, W., P. Kotanko and A. Bazzanella, 1986. Morphological and biochemical observations in rat nephron epithelia following cyclosporine a (CsA) treatment. Clin. Nephrol., 25: 105-110.


  • Mihatsch, M.J., G. Thiel and B. Ryffel, 1988. Histopathology of cyclosporine nephrotoxicity. Transplant. Proc., 20: 759-771.
    PubMed    


  • Deray, G., M. Benhmida, P.L. Hoang, P. Maksud, B. Aupetit, A. Baumelou and C. Jacobs, 1992. Renal function and blood pressure in patients receving long-term low-dose cyclosporine therapy for idiopathi autoimmune uveitis. Ann. Int. Med., 117: 578-583.


  • Kumano, K., K. Yoshida, M. Iwamura, T. Endo, T. Sakai, K. Nakamura and T. Kuwao, 1989. The role for reactive oxygen species in cyclosporin a induced nephrotoxicity in rats. Transplant. Proc., 21: 941-942.


  • Wang, C. and A.K. Salahudeen, 1994. Cyclosporine nephrotoxicity attenuation by an antioxidant-inhibitor of lipid peroxidation In vitro and In vivo. Transplantation, 58: 940-946.
    PubMed    


  • Serino, F., J. Grevel, K.L. Napoli, B.D. Kahan and H.W. Strobel, 1993. Generation of oxygen free radicals during the metabolism of cyclosporine a cause-effect relationship with metabolism inhibition. Mol. Cell. Biochem., 122: 101-112.


  • Suleymanlar, G., I. Suleymanlar, J.I. Shapiro and L. Chan, 1994. Possible role of lipid peroxidation in cyclosporine nephrotoxicity in rats. Transplant Proc., 26: 2888-2889.
    PubMed    


  • Sterrenberg, L., R.H.M. Julicher, A. Bast and J. Noordhoek, 1985. Effect of vitamin E on the balance between pro-and antioxidant activity of ascorbic acid in microsomes from rat heart kidney and liver. Toxicol. Lett., 25: 153-159.
    PubMed    


  • Nath, K.A., M.S. Paller and A.J. Croatt, 1990. Dietary deficiency of antioxidants exacerbates ischemic injury in the rat kidney. Kidney Int., 38: 1109-1117.


  • Lee, H.S., J.Y. Jeong, B.C. Kim, Y.S. Kim, Y.Z. Zhang and H.K. Chung, 1997. Dietary antioxidant inhibits lipoprotein oxidation and renal injury in experimental focal segmental glomerulosclerosis. Kidney Int., 51: 1305-1330.
    Direct Link    


  • Wang, C., A.K. Salahudeen, M. McClain and J. Whitehead, 1995. Lipid peroxidation accompanies cyclosporine nephrotoxicity effect of Vitamin E. Kidney Int., 47: 927-934.
    PubMed    


  • Krysztopik, R.J., F.R. Bentley, D.A. Spain, M.A. Wilson and R.N. Garrison, 1997. Lazaroids prevent acute cyclosporine-induced renal vasoconstriction. Transplantation, 63: 1215-1220.
    Direct Link    


  • Durak, I., H.I. Karabacak, S. Buyukkocak, M.Y.B. Cimen, M. Kacmaz, E. Omeroglu and H.S. Ozturk, 1998. Impaired antioxidant defense system in the kidney tissues from rabbits treated with cyclosporine protective effects of Vitamins E and C. Nephron, 78: 207-211.
    PubMed    


  • Kim, Y.H., S.H. Lee and K.C. Mun, 2002. Effect of melatonin on antioxidant status in the plasma of cylosporine-treated rats. Transplant. Proc., 34: 2652-2653.
    CrossRef    


  • Esrefoglu, M., M. Kurus and E. Sahnah, 2003. The beneficial effect of melatonin on chronic cyclosporin nephrotoxicity in rats. J. Int. Med. Res., 31: 42-44.
    Direct Link    


  • Mascio, P.D., M.E. Murphy and H. Sies, 1991. Antioxidant defense systems the role of carotenoids tocopherols and thiols. Rev. Am. J. Clin. Nutr., 53: 194-200.
    Direct Link    


  • Malhotra, D. and R.E. Wenk, 1993. Cyclosporine-a is a direct toxin to the proximal renal tubular cell. Clin. Res., 41: 98-98.


  • Mihatsch, M.J., B. Ryffel, M. Hermle, F.P. Brunner and G. Thiel, 1986. Morphology of cyclosporine nephrotoxicity in the rat. Clin. Nephrol., 25: 2-8.


  • Sullivan, B.A., L.J. Hak and W.F. Finn, 1985. Cyclosporine nephrotoxicity studies in laboratory animals. Transplant. Proc., 17: 145-154.


  • Humes, H.D. and N.M. Jackson, 1988. Cyclosporine effects on isolated membranes proximal tubule cells and interstitium of the kidney. Transplant. Proc., 20: 748-758.


  • Gillum, D.M., L. Truong and J. Tasby, 1990. Characterization of the interstitial cellular infiltrate in experimental chronic cyclosporine nephropathy. Transplantation, 49: 793-797.
    Direct Link    


  • Weinberg, J.M., 1985. Issues in the pathophysiology of nephrotoxic renal tubular cell injury pertinent to understanding cyclosporine nephrotoxicity. Transplant. Proc., 17: 81-90.


  • Michael, H.R., G.I. Kaye and W. Pawlina, 2003. Histology a Text and Atlas. Lippincott Williams and Wilkins, UK., pp: 602-641


  • Mehring, N., K.H. Neumann, K.H. Rahn and W. Zidek, 1992. Mechanisms of ciclosporin a-induced vasoconstriction in the isolated perfused rat kidney. Nephron, 60: 477-481.
    CrossRef    


  • Zoja, C., L. Furci, F. Ghilardi, P. Zilio, A. Benigni and G. Remuzzi, 1986. Cyclosporin-induced endothelial cell injury. Lab. Invest., 55: 455-462.


  • Sund, S., O. Forre, K.J. Berg, T.K. Kvien and T. Hovig, 1994. Morphological and functional renal effects of long-term low-dose cyclosporin a treatment in patients with rheumatoid arthritis. Clin. Nephrol., 41: 33-40.
    PubMed    


  • Verpooten, G.A., I. Wybo, V.M. Pattyn, P.G. Hendrix and R.A. Giuliano et al., 1986. Cyclosporine nephrotoxicity comparative cytochemical study of rat kidney and human allograft biopsies. Clin. Nephrol., 25: 18-22.
    PubMed    


  • Fasel, J., B. Kaissling, K.S. Ludwig, B. Ryffel and M.J. Mihatsch, 1987. Light and electron microscopic changes in the kidney of wistar rats following treatment with cyclosporine A. Ultrastruct. Pathol., 11: 435-448.
    CrossRef    Direct Link    


  • Mitchell, R.N. and R.S. Cotran, 1997. Repair Cell Regeneration Fibrosis and Wound Healing. In: Basic Pathology, Kumar, V., R.S. Cotran and S.L. Robbins (Eds.). W.B. Saunders Company, Philadelphia, pp: 47-59


  • Al-Qattan, K.K., A.M. Safer and D.K.A. Hajri, 1998. Distention of the lateral intercellular spaces (LIS) in the proximal tubule cells of the non-stenosed kidney of the 2K-1C goldblatt model of hypertension as evidence of pressure diuresis. Anat. Histol. Embryol., 27: 197-204.
    CrossRef    Direct Link    


  • Bertani, T., N. Perico, M. A bbate, C. Battaglia and G. Remuzzi, 1987. Renal injury induced by long-term administration of cyclosporin A to rats. Am. J. Pathol., 127: 569-579.
    PubMed    


  • Mayes, P.A., 1991. Structure and Function of the Lipid-Soluble Vitamins. In: Harpers Biochemistry, Murray, R.K., D.K. Granner, P.A. Mayes and V.W. Rodwell (Eds.). Appleton and Lange, California, pp: 562-570

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