Cyclosporine nephropathy: inhibition of osmoregulatory renal cell transport

The immunosuppressant agent cyclosporine (Sandimmune) is a calmodulin inhibitor that has potent nephrotoxic properties. Recently, it has been observed that osmoregulation in the proximal tubules of the bony fish Carassius auratus (goldfish) is a calmodulin-regulated cell function. As their mammalian counterparts do, these renal tubule cells swell when exposed to hypotonic solutions. This is followed by a slower volume regulatory decrease phase owing to KCl efflux and osmotically obligated water. The extrusion of potassium and chloride is, in this preparation, a calcium and calmodulin regulated process, respectively. With videometric methods, the effects of both cyclosporine (5, 10, and 50 microM) and Cremophor EL (0.65 mg per ml) on osmoregulation were studied in isolated renal tubules. The tubules were stimulated with hypotonic Ringer's solution in the presence and absence of cyclosporine and Cremophor EL. Cremophor EL did not have toxic effects on cell volume regulation; cyclosporine, however, induced a dose-dependent inhibition of osmoregulation. This is due to a hindrance of ionic efflux rather than a decrease in cellular water permeability. It is concluded that the influence of cyclosporine on cell volume control is due to inhibition of the calmodulin-regulated ionic efflux required for osmoregulation.