Nephrol Dial Transplant (2003) 18: 2262-2268
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Cyclosporin A tubular effects contribute to nephrotoxicity: role for Ca2+ and Mg2+ ions
1Nephrology Division, University of Sao Paulo School of Medicine, 2Biophysics Department, UNIFESP and 3Sao Jose do Rio Preto Medical School, Sao Paulo, Brazil
Correspondence and offprint requests to: Luis Yu, MD, Nephrology, LIM 12, University of Sao Paulo, Av. Dr Arnaldo 455 S. 3310, Sao Paulo, Brazil 01246-903. Email: luisyu{at}usp.br
Background. Cyclosporin A (CsA) nephrotoxicity has been attributed primarily to renal haemodynamic alterations caused by afferent arteriolar vasoconstriction. However, CsA nephropathy is also characterized by CsA-induced pre-glomerular disturbances and interstitial injury that may occur independently of haemodynamic changes. Given the high lipophilic activity of CsA, we hypothesized that direct tubular injury is likely to contribute to nephrotoxicity.
Methods. To investigate tubular toxicity of CsA, increasing concentrations of CsA (1, 2.5, 10, 25, 50 and 100 µg/ml) and its vehicle (cremophor) were added to isolated rat proximal tubules (PT). Cell injury was assessed by lactate dehydrogenase (LDH) release. The role of Ca2+ ions in tubular toxicity and the effect of calcium channel blockers on CsA toxicity were evaluated by measuring intracellular calcium using the fluorescent dye Fura-2 AM. The role of Mg2+ ions was assessed using high extracellular Mg2+ medium (2 mM).
Results. Whereas cremophor alone was not toxic to PT, CsA caused PT injury but only at the highest concentration (100 µg/ml). After 90 min incubation, LDH was 22.5% in control PT and 41.9% in PT treated with 100 µg/ml CsA (P < 0.001, n = 11). There was a transient increase in intracellular calcium ([Ca2+]i) after CsA administration. A low calcium medium (100 nM) prevented CsA injury to renal tubules. However, verapamil, but not nifedipine, enhanced cell damage. Only nifedipine completely prevented [Ca2+]i increases following CsA. Finally, a high Mg2+ medium attenuated CsA-induced injury.
Conclusion. We found that high CsA concentrations caused Ca2+- and Mg2+-dependent PT injury. Thus, low extracellular Ca2+ and high Mg2+ media attenuated CsA-induced tubular injury. Verapamil, but not nifedipine, enhanced CsA tubular toxicity. Therefore, CsA-induced tubular injury may contribute to CsA nephrotoxicity independently of haemodynamic disturbances.
Keywords: calcium channel blockers; cyclosporin A; intracellular calcium; magnesium; rat proximal tubules; toxicity
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