Cyclosporine inhibition of the chloride/bicarbonate exchanger of proximal renal tubules.
It has previously been reported by us that the immunosuppressant agent cyclosporine inhibits the ability of renal proximal tubule cells to regulate volume. Proximal renal tubule cells exposed to hypotonic solutions rapidly swell and subsequently shrink. Their regulatory cell volume decrease (RVD) is due to Ca2(+)-calmodulin regulated KCl efflux followed by osmotically obligated water. In proximal renal tubule cells, potassium leaves the cell through a Ca2(+)-activated potassium channel. While it is unknown how the volume regulatory chloride efflux occurs in humans, in teleosts its efflux is through a Cl-/HCO3- anion antiporter. Prior to this work it was known that cyclosporine (CsA) inhibits volume regulation in mammals and teleosts. It was not clear, however, if CsA inhibited the potassium channel, the chloride efflux, or both. In vivo, CsA is a potent calmodulin inhibitor whose effects on cell volume regulation are not mediated by decreased cell water permeability. The effects of the Cl-/OH- antiporter tributyltin (TBT) and the K+ channel gramicidin on CsA-associated RVD inhibition were studied in isolated proximal renal tubules of the teleost Carassius auratus (goldfish). It was found that the inhibitory effect of CsA (50 microM) could be overridden by the administration of TBT (1 microM) but could not be modified by the potassium ionophore gramicidin (0.5 microM). The inhibitory effect of CsA could not be altered by increased Ca2+ influx through the Ca2+ ionophore A23817 (10 microM), and, therefore, an altered calcium activation of KCl efflux does not appear to be involved. In conclusion, the CsA effect on RVD is due to a selective inhibition of chloride efflux most likely mediated by inhibition of the cyclophilin-calmodulin system and not by a decreased intracellular calcium signal.
Kanli
H
H
Department of Pathology, University of Utah, Salt Lake City.
Terreros
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D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D027963:Chloride-Bicarbonate Antiporters; D003524:Cyclosporins / Q000494:pharmacology*; D006054:Goldfish / Q000378:metabolism*; D006096:Gramicidin / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009994:Osmolar Concentration; D014220:Trialkyltin Compounds / Q000494:pharmacology
D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D003524:Cyclosporins; D014220:Trialkyltin Compounds; D006096:Gramicidin; D000001:Calcimycin; C011559:tributyltin