BACKGROUND: Cyclosporine A (CsA) is an immunosuppressive drug used to prevent tissue allograft rejection. However, its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available. This study evaluated the effect of spironolactone on renal functional and structural alterations induced by CsA, and assessed whether the protective effect was associated with a reduction of transforming growth factor-beta (TGF-beta) and the change of extracellular matrix protein mRNA level. METHODS: Male Wistar rats fed with low sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg), spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine clearance (CCr), blood CsA, arteriolopathy in renal tissue, and TGF-beta, collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA levels in renal cortex were determined. RESULTS: CsA reduced the CCr and up-regulated TGF-beta, collagen I and fibronectin mRNA expression with a significant development of arteriolopathy, and reduced EGF mRNA levels. In contrast, spironolactone administration prevented the fall in renal function and TGF-beta, collagen I, and fibronectin up-regulation, together with a reduction of arteriolopathy and tubulointerstitial fibrosis. CONCLUSION: Our data show that aldosterone plays an important role as a mediator of renal injury induced by CsA. Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent CsA nephrotoxicity.
BACKGROUND:Cyclosporine A (CsA) is an immunosuppressive drug used to prevent tissue allograft rejection. However, its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available. This study evaluated the effect of spironolactone on renal functional and structural alterations induced by CsA, and assessed whether the protective effect was associated with a reduction of transforming growth factor-beta (TGF-beta) and the change of extracellular matrix protein mRNA level. METHODS: Male Wistar rats fed with low sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg), spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine clearance (CCr), blood CsA, arteriolopathy in renal tissue, and TGF-beta, collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA levels in renal cortex were determined. RESULTS:CsA reduced the CCr and up-regulated TGF-beta, collagen I and fibronectin mRNA expression with a significant development of arteriolopathy, and reduced EGF mRNA levels. In contrast, spironolactone administration prevented the fall in renal function and TGF-beta, collagen I, and fibronectin up-regulation, together with a reduction of arteriolopathy and tubulointerstitial fibrosis. CONCLUSION: Our data show that aldosterone plays an important role as a mediator of renal injury induced by CsA. Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent CsAnephrotoxicity.
Authors: Cristian A Amador; Jean-Philippe Bertocchio; Gwennan Andre-Gregoire; Sandrine Placier; Jean-Paul Duong Van Huyen; Soumaya El Moghrabi; Stefan Berger; David G Warnock; Christos Chatziantoniou; Iris Z Jaffe; Philippe Rieu; Frederic Jaisser Journal: Kidney Int Date: 2016-02 Impact factor: 10.612
Authors: Mara Medeiros; Luis Velásquez-Jones; Ana M Hernández; Guillermo Ramón-García; Saúl Valverde; Yolanda Fuentes; Arindal Vargas; Mauricio Patiño; Rosalba Pérez-Villalva; Juan Antonio Ortega-Trejo; Jonatan Barrera-Chimal; Norma A Bobadilla Journal: Clin J Am Soc Nephrol Date: 2017-05-23 Impact factor: 8.237
Authors: Finn Thomsen Nielsen; Boye L Jensen; Pernille B L Hansen; Niels Marcussen; Peter Bie Journal: BMC Nephrol Date: 2013-02-20 Impact factor: 2.388