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Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Renal+Physiol 2020 ; 319 (3): F534-F540 Nephropedia Template TP
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Distal convoluted tubule Cl(-) concentration is modulated via K(+) channels and transporters #MMPMID32715757
Su XT; Klett NJ; Sharma A; Allen CN; Wang WH; Yang CL; Ellison DH
Am J Physiol Renal Physiol 2020[Sep]; 319 (3): F534-F540 PMID32715757show ga
Cl(-)-sensitive with-no-lysine kinase (WNK) plays a key role in regulating the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT). Cl(-) enters DCT cells through NCC and leaves the cell across the basolateral membrane via the Cl(-) channel ClC-K2 or K(+)-Cl(-) cotransporter (KCC). While KCC is electroneutral, Cl(-) exit via ClC-K2 is electrogenic. Therefore, an alteration in DCT basolateral K(+) channel activity is expected to influence Cl(-) movement across the basolateral membrane. Although a role for intracellular Cl(-) in the regulation of WNK and NCC has been established, intracellular Cl(-) concentrations ([Cl(-)](i)) have not been directly measured in the mammalian DCT. Therefore, to measure [Cl(-)](i) in DCT cells, we generated a transgenic mouse model expressing an optogenetic kidney-specific Cl-Sensor and measured Cl(-) fluorescent imaging in the isolated DCT. Basal measurements indicated that the mean [Cl(-)](i) was ~7 mM. Stimulation of Cl(-) exit with low-Cl(-) hypotonic solutions decreased [Cl(-)](i), whereas inhibition of KCC by DIOA or inhibition of ClC-K2 by NPPB increased [Cl(-)](i), suggesting roles for both KCC and ClC-K2 in the modulation of [Cl(-)](i) . Blockade of basolateral K(+) channels (Kir4.1/5.1) with barium significantly increased [Cl(-)](i). Finally, a decrease in extracellular K(+) concentration transiently decreased [Cl(-)](i), whereas raising extracellular K(+) transiently increased [Cl(-)](i), further suggesting a role for Kir4.1/5.1 in the regulation of [Cl(-)](i). We conclude that the alteration in ClC-K2, KCC, and Kir4.1/5.1 activity influences [Cl(-)](i) in the DCT.