A new perception of the role of aldosterone in the pathophysiology of chronic nephrotoxicity induced by cyclosporine
Abstract
Cyclosporine A (CsA) is a calcineurin inhibitor widely use to prevent organ transplant rejection and for treating autoimmune diseases. Since CsA introduction, organ transplant and patient survival significantly increased and this outcome has not been modified by the new immunosuppressive agents. The long use of CsA, however has been limited because its nephrotoxic side effect. Two forms of renal toxicity have been described, the acute and the chronic toxicty. Acute nephrotoxicity is characterized by renal dysfunction produced by an increase in vasoconstrictor factors that is reversible if CsA dose is reduced or even more if it is withdrawal. Whereas, chronic CsA nephrotoxicity is characterized by renal vasoconstriction and the concomitant development of arteriolopathy and tubulo-interstitial fibrosis. This form is non-reversible and might progress to chronic renal insufficiency.Although the exact mechanisms by which CsA induced renal damage are not completely established, several advances have made to prevent CsA nephrotoxity. This review discusses the pathophysiology and the pharmacological strategies proved to reduce this CsA nephropathy, emphasizing the studies that have concentrated to study the effect of mineralocorticoid receptors blockade during the renal injury induced by CsA.
References
de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis. 2000;35(2):333-46.
Yoshimoto T, Hirata Y. Aldosterone as a cardiovascular risk hormone. Endocr J. 2007;54(3):359-70.
Björnholm M, Münzberg H, Leshan RL, Villanueva EC, Bates SH, Louis GW, et al. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. Clin Invest. 2007;117(5):1354-60.
Campistol JM, Sacks SH. Mechanisms of nephrotoxicity. Transplantation. 2000;69(12 Suppl):SS5-10.
Cohen MP, Chen S, Ziyadeh FN, Shea E, Hud EA, Lautenslager GT, et al. Evidence linking glycated albumin to altered glomerular nephrin and VEGF expression, proteinuria, and diabetic nephropathy. Kidney Int. 2005;68(4):1554-61.
Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326-33.
Kopp JB, Klotman PE. Cellular and molecular mechanisms of cyclosporin nephrotoxicity. J Am Soc Nephrol. 1990;1(2):162-79.
Jackson NM, Hsu CH, Visscher GE, Venkatachalam MA, Humes HD. Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity. J Pharmacol Exp Ther. 1987;242(2):749-56.
Elzinga LW, Rosen S, Bennett WM. Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J Am Soc Nephrol. 1993;4(2):214-21.
Schwedler SB, Bobadilla N, Striker LJ, Vaamonde CA, Herrera-Acosta J, Striker GE. Pentosan polysulfate treatment reduces cyclosporine-induced nephropathy in salt-depleted rats. Transplantation. 1999;68(10):1583-8.
Feria I, Pichardo I, Juárez P, Ramírez V, González MA, Uribe N, et al. Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity. Kidney Int. 2003;63(1):43-52.
Pérez-Rojas JM, Derive S, Blanco JA, Cruz C, Martínez de la Maza L, Gamba G, et al. Renocortical mRNA expression of vasoactive factors during spironolactone protective effect in chronic cyclosporine nephrotoxicity. Am J Physiol Renal Physiol. 2005;289(5):F1020-30.
Barros EJ, Boim MA, Ajzen H, Ramos OL, Schor N. Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity. Kidney Int. 1987;32(1):19-25.
Bobadilla NA, Tapia E, Franco M, López P, Mendoza S, García-Torres R, et al. Role of nitric oxide in renal hemodynamic abnormalities of cyclosporin nephrotoxicity. Kidney Int. 1994;46(3):773-9.
Bobadilla NA, Gamba G, Tapia E, García-Torres R, Bolio A, López-Zetina P, et al. Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression. Am J Physiol. 1998;274(4):F791-8.
Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL. Role of endothelin in cyclosporine-induced glomerular dysfunction.
Kidney Int. 1990;37(6):1487-91.
Perico N, Benigni A, Zoja C, Delaini F, Remuzzi G. Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A. Am J Physiol. 1986;251(4 Pt 2):F581-7.
Perico N, Benigni A, Bosco E, Rossini M, Orisio S, Ghilardi F, et al. Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins? Clin Nephrol. 1986;(25 Suppl. 1):S83-8.
Thomson AW, McAuley FT, Whiting PH, Simpson JG. Angiotensin-converting enzyme inhibition or aldosterone antagonism reduces cyclosporine nephrotoxicity in the rat. Transplant Proc. 1987;19(1 Pt 2):1242-3.
Diederich D, Yang Z, Lüscher TF. Chronic cyclosporine therapy impairs endothelium-dependent relaxation in the renal artery of the rat. J Am Soc Nephrol. 1992;2(8):1291-7.
Vaziri ND, Ni Z, Zhang YP, Ruzics EP, Maleki P, Ding Y. Depressed renal and vascular nitric oxide synthase expression in cyclosporine-induced hypertension. Kidney Int. 1998;54(2):482-91.
López-Ongil S, Saura M, Rodríguez-Puyol D, Rodríguez-Puyol M, Lamas S. Regulation of endothelial NO synthase expression by cyclosporin A in bovine aortic endothelial cells. Am J Physiol. 1996;271(3 Pt 2):H1072-8.
Pichler RH, Franceschini N, Young BA, Hugo C, Andoh TF, Burdmann EA, et al. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol. 1995;6(4):1186-96.
Shihab FS, Bennett WM, Tanner AM, Andoh TF. Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy. Kidney Int. 1997;52(3):660-73.
Zhong Z, Arteel GE, Connor HD, Yin M, Frankenberg MV, Stachlewitz RF, et al. Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Physiol. 1998;275(4):F595-604.
Zhong Z, Connor HD, Yin M, Moss N, Mason RP, Bunzendahl H, et al. Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney. Mol Pharmacol. 1999;56(3):455-63.
Vieira JM Jr, Noronha IL, Malheiros DM, Burdmann EA. Cyclosporine-induced interstitial fibrosis and arteriolar TGF-beta expression with preserved renal blood flow. Transplantation. 1999;68(11):1746-53.
Ling H, Li X, Jha S, Wang W, Karetskaya L, Pratt B, et al. Therapeutic role of TGF-beta-neutralizing antibody in mouse cyclosporin A nephropathy: morphologic improvement associated with functional preservation. J Am Soc Nephrol. 2003;14(2):377-88.
Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, et al. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int. 1998;53(4):897-908.
Hunley TE1, Fogo A, Iwasaki S, Kon V. Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity. J Am Soc Nephrol. 1995;5(9):1718-23.
Andoh TF, Gardner MP, Bennett WM. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation. 1997;64(9):1236-40.
Shihab FS, Bennett WM, Isaac J, Yi H, Andoh TF. Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity. Kidney Int. 2003;63(2):522-33.
Venema RC, Venema VJ, Ju H, Harris MB, Snead C, Jilling T, et al. Novel complexes of guanylate cyclase with heat shock protein 90 and nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2003;285(2):H669-78.
Shihab FS, Bennett WM, Yi H, Andoh TF. Effect of pirfenidone on apoptosis-regulatory genes in chronic cyclosporine nephrotoxicity. Transplantation. 2005;79(4):419-26.
Shihab FS, Bennett WM, Yi H, Andoh TF. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant. 2002;2(2):111-9.
Mizui M, Isaka Y, Takabatake Y, Mizuno S, Nakamura T, Ito T, et al. Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity. Kidney Int. 2004;65(6):2041-53.
Shihab FS, Bennett WM, Yi H, Choi SO, Andoh TF. Mycophenolate mofetil ameliorates arteriolopathy and decreases transforming growth factor-beta1 in chronic cyclosporine nephrotoxicity. Am J Transplant. 2003;3(12):1550-9.
Arya R, Mallik M, Lakhotia SC. Heat shock genes - integrating cell survival and death. J Biosci. 2007;32(3):595-610.
Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, et al. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation. 2002;74(6):784-91.
Nielsen J, Kwon TH, Frøkiaer J, Knepper MA, Nielsen S. Maintained ENaC trafficking in aldosterone-infused rats during mineralocorticoid and glucocorticoid receptor blockade. Am J Physiol Renal Physiol. 2007;292(1):F382-94.
Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett WM. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int. 1996;50(4):1110-7.
McCulloch TA, Harper SJ, Donnelly PK, Moorhouse J, Bell PR, Walls J, et al. Influence of nifedipine on interstitial fibrosis in renal transplant allografts treated with cyclosporin A. J Clin Pathol. 1994;47(9): 839-42.
Bobadilla NA, Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone. Am J Physiol Renal Physiol. 2007;293(1):F2-9.
Mejía-Vilet JM, Ramírez V, Cruz C, Uribe N, Gamba G, Bobadilla NA. Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone. Am J Physiol Renal Physiol. 2007;293(1):F78-86.
Stanton B, Giebisch G, Klein-Robbenhaar G, Wade J, DeFronzo RA. Effects of adrenalectomy and chronic adrenal corticosteroid replacement on potassium transport in rat kidney. J Clin Invest. 1985;75(4):1317-26.
Velarde V, Ullian ME, Morinelli TA, Mayfield RK, Jaffa AA. Mechanisms of MAPK activation by bradykinin in vascular smooth muscle cells. Am J Physiol. 1999;277(2):C253-61.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-17.
Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, et al. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology. 2000;141(10):3871-8.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-21.
Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol. 2006;1(2):256-62.
Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med. 2001;345(12):925-6.
Hostetter TH, Ibrahim HN. Aldosterone in chronic kidney and cardiac disease. J Am Soc Nephrol. 2003;14(9):2395-401.
Joffe HV, Adler GK. Effect of aldosterone and mineralocorticoid receptor blockade on vascular inflammation. Heart Fail Rev. 2005;10(1):31-7.
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest. 1996;98(4):1063-8.
Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension. 1998;31(1 Pt 2):451-8.
Blasi ER, Rocha R, Rudolph AE, Blomme EA, Polly ML, McMahon EG. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003;63(5):1791-800.
Rocha R, Chander PN, Zuckerman A, Stier CT Jr. Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension. 1999;33(1 Pt 2):232-7.
Trachtman H, Weiser AC, Valderrama E, Morgado M, Palmer LS. Prevention of renal fibrosis by spironolactone in mice with complete unilateral ureteral obstruction. J Urol. 2004;172(4 Pt 2):1590-4.
Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int. 2004;66(1):1-9.
Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006;17(5):1362-72.
Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology. 2006;147(11):5363-73.
Juknevicius I, Segal Y, Kren S, Lee R, Hostetter TH. Effect of aldosterone on renal transforming growth factor-beta. Am J Physiol Renal Physiol. 2004;286(6):F1059-62.
Sato A, Hayashi K, Saruta T. Antiproteinuric effects of
mineralocorticoid receptor blockade in patients with chronic renal disease. Am J Hypertens. 2005;18(1):44-9.
Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis. 2005;46(1):45-51.
Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper MA. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. J Clin Invest. 1999;104(7):R19-23.
Kim GH, Masilamani S, Turner R, Mitchell C, Wade JB, Knepper MA. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci U S A. 1998;95(24):14552-7.
Schiffrin EL, Gutkowska J, Genest J. Effect of angiotensin II and deoxycorticosterone infusion on vascular angiotensin II receptors in rats. Am J Physiol. 1984;246(4 Pt 2):H608-14.
Ngarmukos C, Grekin RJ. Nontraditional aspects of aldosterone physiology. Am J Physiol Endocrinol Metab. 2001;281(6):E1122-7.
Gooch JL, Gorin Y, Zhang BX, Abboud HE. Involvement of calcineurin in transforming growth factor-beta-mediated regulation of extracellular matrix accumulation. J Biol Chem. 2004;279(15):15561-70.
Pérez-Rojas J, Blanco JA, Cruz C, Trujillo J, Vaidya VS, Uribe N, et al. Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am J Physiol Renal Physiol. 2007;292(1):F131-9.
Arima S, Kohagura K, Xu HL, Sugawara A, Abe T, Satoh F, et al. Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol. 2003;14(9):2255-63.
Gros R, Ding Q, Armstrong S, O'Neil C, Pickering JG, Feldman RD. Rapid effects of aldosterone on clonal human vascular smooth muscle cells. Am J Physiol Cell Physiol. 2007;292(2):C788-94.
Quaschning T, Voss F, Relle K, Kalk P, Vignon-Zellweger N, Pfab T, et al. Lack of endothelial nitric oxide synthase promotes endothelin-induced hypertension: lessons from endothelin-1 transgenic/endothelial nitric oxide synthase knockout mice. J Am Soc Nephrol. 2007;18(3):730-40.
Kramer AB, van der Meulen EF, Hamming I, van Goor H, Navis G. Effect of combining ACE inhibition with aldosterone blockade on proteinuria and renal damage in experimental nephrosis. Kidney Int. 2007;71(5):417-24.
Wang W, McClain JM, Zucker IH. Aldosterone reduces baroreceptor discharge in the dog. Hypertension. 1992;19(3):270-7.
Schiffrin EL, Franks DJ, Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can J Physiol Pharmacol. 1985;63(12):1522-7.
Wu MS, Yang CW, Chang CT, Bens M, Vandewalle A. Cyclosporin increases the density of angiotensin II subtype 1 (AT1) receptors in mouse medullary thick ascending limb cells. Nephrol Dial Transplant. 2003;18(8):1458-65.
Xiao F, Puddefoot JR, Barker S, Vinson GP. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension. 2004;44(3):340-5.
Leopold JA, Dam A, Maron BA, Scribner AW, Liao R, Handy DE, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007;13(2):189-97.
Tait SA, Tait JF. The correspondence of S.A.S. Simpson and J.F. Tait with T. Reichstein during their collaborative work on the isolation and elucidation of the structure of electrocortin (later aldosterone). Steroids. 1998;63(9):440-53.
Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol. 2003;23(5):465-76.
Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care. 2001;7(6):384-9.
Li C, Yang CW, Park JH, Lim SW, Sun BK, Jung JY, et al. Pravastatin treatment attenuates interstitial inflammation and fibrosis in a rat model of chronic cyclosporine-induced nephropathy. Am J Physiol Renal Physiol. 2004;286(1):F46-57.
