Different effects of Cyclosporine‐A and FK506 on aquaporin‐2 expression

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Immunosuppressive drugs like Cyclosporine‐A (CyA) and FK506, both calcineurin inhibitors, are used to silence the immune system after transplantation. Both drugs have often complex side effects. For example long term treatment with CyA is followed by down‐regulation of aquaporin‐2 (AQP2) at least in the rat kidney. To investigate if CyA directly influences the expression of AQP2 we used primary cultured rat inner medullary collecting duct cells (IMCD), which endogenously express AQP2 and AVP‐mediated regulation of AQP2. IMCD‐cells were treated for different time‐periods with different concentrations of CyA or FK506. We used real‐time PCR to analyze mRNA expression levels of AQP2. Treatment with 0.5 μM, 1 μM or 5 μM CyA for 30 min and for 48 h was followed by concentration and time dependent down‐regulation of AQP2 expression. In contrast treatment with FK506 (1 μM, 30 min and 48 h) showed no effect on AQP2 expression. CyA had no effect on expression and activity of the tonicity element binding protein (TonEBP), a factor involved in AQP2 mRNA expression. But CyA suppressed also the cAMP induced expression of AQP2. In conclusion our results showed that CyA directly down‐regulates the expression of AQP2 in IMCD cells. Our data indicate that the underlying mechanism is calcineurin and TonEBP independent and that the down‐regulation of AQP2 is due to a disturbance of cAMP signaling induced by CyA.