The effect of Ca2+ and calcimimetics on NaCl transport was investigated in the in vitro isolated microperfused mouse thin ascending limb of Henle's loop. In the presence of a transmural NaCl gradient, the transepithelial diffusional potential was 13.7±0.4 mV (n=17). When the Ca2+ in the bath was increased from 1.5 to 4.5 mM at 37°C, the relative permeability of Na+ to Cl- (P Na /P Cl) estimated from the diffusional voltage deflection due to the transepithelial NaCl gradient (V d) changed from 0.371±0.017 to 0.341±0.015 (n=10, P<0.0001). When the Ca2+ in the lumen was increased from 1.5 to 4.5 mM, the P Na /P Cl decreased from 0.349±0.013 to 0.330±0.013 (n=5, P<0.002). The addition of 0.1 mM neomycin and 0.2 mM gentamicin to the bath or lumen also decreased the P Na /P Cl. The same effect on P Na /P Cl of Ca2+ and calcimimetics occurred in ClC-K1 (kidney-specific chloride channel) knockout mice. The addition of 300 μg/ml protamine to the bath strongly inhibited changes to P Na /P Cl induced by basolateral Ca2+. These data indicate that ambient Ca2+ and calcimimetics inhibit Na+ transport in the thin ascending limb, which is known to occur via the paracellular shunt pathway. Our observations strongly suggest that Ca2+ is involved in the regulation of paracellular Na+ permeability in the thin ascending limbs.
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