NYMC Faculty Publications

Title

Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule

Document Type

Article

Publication Date

January 2019

Department

Pharmacology

Abstract

The stimulation of beta-adrenergic receptor increases thiazide-sensitive NaCl cotransporter (NCC), an effect contributing to salt-sensitive hypertension by sympathetic stimulation. We now test whether the stimulation of beta-adrenergic receptor-induced activation of NCC is achieved through activating basolateral Kir4.1 in the distal convoluted tubule (DCT). Application of norepinephrine increased the basolateral 40 pS K(+) channel (Kir4.1/Kir5.1 heterotetramer) in the DCT. The stimulatory effect of norepinephrine on the K(+) channel was mimicked by cAMP analogue but abolished by inhibiting PKA (protein kinase A). Also, the effect of norepinephrine on the K(+) channel in the DCT was recapitulated by isoproterenol but not by alpha-adrenergic agonist and blocked by propranolol, suggesting that norepinephrine effect on the K(+) channel was mediated by beta-adrenergic receptor. The whole-cell recording shows that norepinephrine and isoproterenol increased DCT K(+) currents and shifted the K(+) current ( IK) reversal potential to negative range (hyperpolarization). Continuous norepinephrine perfusion (7 days) increased DCT K(+) currents, hyperpolarized IK reversal potential, and increased the expression of total NCC/phosphorylated NCC, but it had no significant effect on the expression of NKCC2 (type 2 Na-Cl-K cotransporter) and ENaC-alpha (epithelial Na channel-alpha subunit). Renal clearance study demonstrated that norepinephrine perfusion augmented thiazide-induced urinary Na(+) excretion only in wild-type but not in kidney-specific Kir4.1 knockout mice, suggesting that Kir4.1 is required for mediating the effect of norepinephrine on NCC. However, norepinephrine perfusion did not affect urinary K(+) excretion. We conclude that the stimulation of beta-adrenergic receptor activates the basolateral Kir4.1 in the DCT and that the activation of Kir4.1 is required for norepinephrine-induced stimulation of NCC.

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