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CyA-Mediated Renal Interstitial and Vascular Lesions in the Rat under Low-Sodium Diet

First Department of Pathology, Shinshu University, School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan

Takashi Ehara

First Department of Pathology, Shinshu University, School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan

Nephrotoxicity of CyA was analyzed histologically in rats fed a low-sodium diet. CyA was subcutaneously administered daily at a dose of 15 mg/kg for 10 or 35 days with or without prior uninephrectomy (UNT) in male Sprague-Dawley rats receiving a low-sodium diet (0.03% sodium). CyA-administered rats showed impaired renal function as well as tubulo-interstitial lesions, such as edema, tubular basement membrane changes, and tubular atrophy, in the cortex, especially in the subcapsular portion, within 10 days. On day 35, the tubulo-interstitial lesions were advanced with mild focal interstitial fibrosis. These lesions were mild in the UNT group compared to the non-UNT group. Immunohistochemically, CyA treatment caused an increase in number of renin-positive cells in the afferent arteriolar wall at juxtaglomerular area. These cells lost the expression of calponin, which is a marker of mature smooth muscle cells. In addition, in afferent arterioles and interlobular arteries, electron-dense fibrous bodies were found in the smooth muscle cells on days 10 and 35. Immunoelectron microscopically, these bodies showed scattered positive staining for calponin and -actinin, were negative or only peripherally positive for -SMA and vimentin, and were completely negative for desmin. This study revealed that CyA could cause interstitial lesions starting in the subcapsular portion of the renal cortex and vascular lesions of the preglomerular artery. Increases in number of renin granules and formation of cytoplasmic fibrous bodies in smooth muscle cells could be the forerunner of severe arteriolar wall damage.

Key Words: Cyclosporine • low-sodium diet • rats • uninephrectomy • nephrotoxicity • vascular lesions • subcapsular lesions

References

• Andoh TF, Lam TT, Lindsley J., Alpers CE, Bennett WM (1997). Enhancement of chronic cyclosporine nephrotoxicity by sodium depletion in an experimental mouse model. Nephrology 3: 471-478.[CrossRef]
• Barajas L. (1979). Anatomy of the juxtaglomerular apparatus (editorial review). Am J Physiol 237: F333-F343.[Web of Science][Medline] [Order article via Infotrieve]
• Border WA, Noble NA (1994). Transforming growth factor β in tissue fibrosis. N Engl J Med 331: 1286-1292.[Free Full Text]
• Cattell V. (1994). Macrophages in acute glomerular inflammation (editorial review). Kidney Int 45: 945-952.[Web of Science][Medline] [Order article via Infotrieve]
• Cavarape A., Endlich K., Feletto F., Parekh N., Bartoli E., Steinhausen M. (1998). Contribution of endothelin receptors in renal microvessels in acute cyclosporine-mediated vasoconstriction in rats. Kidney Int 53: 963-969.[Web of Science][Medline] [Order article via Infotrieve]
• Elzinga LW, Rosen S., Bennett WM (1993). Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: Role of sodium intake. J Am Soc Nephrol 4: 214-221.[Abstract]
• English J. Evan A. Houghton DC, Bennett WM (1987). Cyclosporine-induced acute renal dysfunction in the rat. Transplantation 44: 135-141.[Web of Science][Medline] [Order article via Infotrieve]
• Fasel J., Kaissling B. Ludwig KS, Ryffel B., Mihatsch MJ (1987). Light and electron microscopic changes in the kidney of Wistar rats following treatment with cyclosporine A. Ultrastruct Pathol 11: 435-448.[Web of Science][Medline] [Order article via Infotrieve]
• Fried TA, Hishida A., Barnes JL, Stein JH (1984). Ischemic acute renal failure in the rat: Protective effect of uninephrectomy. Am J Physiol 247: F568-F574.[Web of Science][Medline] [Order article via Infotrieve]
• Ghiggeri GM, Altieri P., Oleggini R., Valenti F., Ginevri F., Perfumo F., Gusmano R. (1994). Cyclosporine enhances the synthesis of selected extracellular matrix proteins by renal cells "in culture." Transplantation 57: 1382-1388.[Web of Science][Medline] [Order article via Infotrieve]
• Gimona M., Herzog M., Vandekerckhove J., Small JV (1990). Smooth muscle specific expression of calponin. FEBS Lett 274: 159-162.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kato A., Hishida A., Tanaka I., Komatsu K. (1997). Uninephrectomy prevents the ischemia-induced increase in renin activity. Nephron 75: 72-76.[Web of Science][Medline] [Order article via Infotrieve]
• Kimura K., Nagai R., Sakai T., et al (14 coauthors) (1995). Diversity and variability of smooth muscle phenotypes of renal arterioles as revealed by myosin isoform expression. Kidney Int 48: 372-382.[Web of Science][Medline] [Order article via Infotrieve]
• Kokui K., Yoshikawa N., Nakamura H., Itoh H. ( 1992). Cyclosporin reduces proteinuria in rats with aminonucleoside nephrosis. J Pathol 166: 297-301.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kon V., Hunley TE, Fogo A. ( 1995). Combined antagonism of endothelin A/B receptors links endothelin to vasoconstriction whereas angiotensin II effects fibrosis. Transplantation 60: 89-95.[Web of Science][Medline] [Order article via Infotrieve]
• Lee Dbn (1997). Cyclosporine and the renin-angiotensin axis. Kidney Int 52: 248-260.[Web of Science][Medline] [Order article via Infotrieve]
• Liu A., Ballermann BJ (1998). TGF-β type II receptor in rat renal vascular development: Localization to juxtaglomerular cells. Kidney Int 53: 716-725.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Martin A., Wong K-S., Li M., Turner SW, Whitworth JA (1994). Cyclosporin hypertension in the wistar rat: Role of uninephrectomy. Clin Exp Pharmacol Physiol 21: 287-292.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Mason J., Müller-Schweinitzer E., Dupont M., Casellas D., Mihatsch M., Moore L., Kaskel F. (1991). Cyclosporine and the renin-angiotensin system. Kidney Int 39: S28-S32.[Web of Science]
• Medina J., Cordier A., Wolf A. ( 1997). Cyclosporine A-induced contraction of isolated rat aortic smooth muscle cells. Life Sci 61: PL327-PL332.[CrossRef][Web of Science]
• Mihatsch MJ, Thiel G., Spichtin HP, Oberholzer M., Brunner FP, Harder F., Olivieri V., Bremer R., Ryffel B., Stöcklin E., Torhorst J., Gudat F., Zollinger HU, Loertscher R. (1983). Morphological findings in kidney transplants after treatment with cyclosporine. Transplant Proc 15(suppl 1): 2821-2835.[Web of Science]
• Myers BD, Sibley R., Newton L., Tomlanovich SJ, Boshkos C., Stinson E., Luetscher JA, Whitney DJ, Krasny D., Coplon NS, Perlroth MG (1988). The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int 33: 590-600.[Web of Science][Medline] [Order article via Infotrieve]
• Niaudet P. (1995). Cyclosporine in the treatment of idiopathic nephrosis. Indian Pediatr 32: 1317-1321.[Medline] [Order article via Infotrieve]
• North AJ, Gimona M., Cross RA, Small JV (1994). Calponin is localised in both the contractile apparatus and the cytoskeleton of smooth muscle cells. J Cell Sci 107: 437-444.[Abstract]
• Pimentel JL Jr, Sundell CL, Wang S., Kopp JB, Montero A., Martinez-Maldonado M. (1995 ). Role of angiotensin II in the expression and regulation of transforming growth factor-β in obstructive nephropathy. Kidney Int 48: 1233-1246.[Web of Science][Medline] [Order article via Infotrieve]
• Ponticelli C., Rizzoni G., Edefonti A., Altieri P., Rivolta E., Rinaldi S., Ghio L., Lusvarghi E., Gusmano R., Locatelli F. Pasquali S, Castellani A., Casa-Alberighi OD (1993). A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome. Kidney Int 43: 1377-1384.[Web of Science][Medline] [Order article via Infotrieve]
• Rolls KA, Phillips PA. Aldred K., Hardy KJ (1994). Vasoconstrictor responses to components of the renin-angiotensin system in cyclosporin-induced hypertension in the rat. Clin Exp Pharmacol Physiol 21: 227-230.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Rosen S., Greenfeld Z., Brezis M. (1990). Chronic cyclosporine-induced nephropathy in the rat. Transplantation 49: 445-452.[Web of Science][Medline] [Order article via Infotrieve]
• Roullet J-B., Xue H., McCarron DA, Holcomb S., Bennett WM (1994). Vascular mechanisms of cyclosporin-induced hypertension in the rat. J Clin Invest 93: 2244-2250.[Web of Science][Medline] [Order article via Infotrieve]
• Ryffel B., Siegl H., Petric R., Muller AM, Hauser R., Mihatsch MJ (1986). Nephrotoxicity of cyclosporine in spontaneously hypertensive rats: Effects on blood pressure and vascular lesions. Clin Nephrol 25(suppl 1): S193-S198.[Web of Science][Medline] [Order article via Infotrieve]
• Seppo T., Tero S., Tapio N. (1989). Ultrastructural, immunochemical and electrophoretic study of smooth muscle cells in internal mammary arteries of patients undergoing coronary bypass surgery. Atherosclerosis 79: 129-138.[CrossRef][Medline] [Order article via Infotrieve]
• Shanley PF (1996). The pathology of chronic renal ischemia. Semin Nephrol 16: 21-32.[Web of Science][Medline] [Order article via Infotrieve]
• Shehata M., Cope GH, Johnson TS, Raftery AT, El Nahas AM (1995). Cyclosporine enhances the expression of TGF-β in the juxtaglomerular cells of the rat kidney. Kidney Int 48: 1487-1496.[Web of Science][Medline] [Order article via Infotrieve]
• Shihab FS (1996). Cyclosporine nephropathy: Pathophysiology and clinical impact. Semin Nephrol 16: 536-547.[Web of Science][Medline] [Order article via Infotrieve]
• Shihab FS, Bennett WM, Tanner AM, Andoh TF (1997). Angiotensin II blockade decreases TGF-β1 and matrix proteins in cyclosporine nephropathy. Kidney Int 52: 660-673.[Web of Science][Medline] [Order article via Infotrieve]
• Simpson JG, Saunders NJ, Thomson KJ, Whiting PH (1988). Chronic renal damage caused by cyclosporine. Transplant Proc 20(suppl 3): 792-799.[Web of Science][Medline] [Order article via Infotrieve]
• Strm EH, Epper R., Mihatsch MJ (1995). Ciclosporin-associated arteriolopathy: The renin producing vascular smooth muscle cells are more sensitive to ciclosporin toxicity. Clin Nephrol 43: 226-231.[Web of Science][Medline] [Order article via Infotrieve]
• Stromer MH (1995). Immunocytochemistry of the muscle cell cytoskeleton. Microsc Res Tech 31: 95-105.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Vernetti LA, Gandolfi AJ, Nagle RB (1991). Selective alteration of cytokeratin intermediate filament by cyclosporine A is a lethal toxicity in PtK2 cell cultures. Adv Exp Med Biol 283: 847-851.[Medline] [Order article via Infotrieve]
• von Graffenried B., Friend D., Shand N., Schiess W., Timonen P. (1989). Cyclosporin A (Sandimmun®) in autoimmune disorders. In: Cyclosporin, Thomson AW (ed). Kluwer Academic, Dordrecht, pp 213-251.
• Young BA, Burdmann EA, Johnson RJ, Alpers CE, Giachelli CM, Eng E., Andoh T., Bennett WM, Couser WG (1995). Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int 48: 439-448.[Web of Science][Medline] [Order article via Infotrieve]
• Young BA, Burdmann EA, Johnson RJ, Andoh T., Bennett WM, Couser WG, Alpers CE (1995). Cyclosporine A induced arteriolopathy in a rat model of chronic cyclosporine nephropathy. Kidney Int 48: 431-438.[Web of Science][Medline] [Order article via Infotrieve]
• Zoja C., Furci L., Ghilardi F., Zilio P., Benigni A., Remuzzi G. (1986). Cyclosporin-induced endothelial cell injury. Lab Invest 55: 455-462.[Web of Science][Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 28, No. 4, 518-528 (2000)
DOI: 10.1177/019262330002800403


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Nagasawa, T. Articles by Ehara, T. Search for Related Content PubMed PubMed Citation Articles by Nagasawa, T. Articles by Ehara, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CYCLOSPORIN A Medline Plus Health Information Diets Vascular Diseases Social Bookmarking                         What's this?