NYMC Faculty Publications
Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule
Journal Title
Hypertension
First Page
112
Last Page
120
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.
Recommended Citation
Duan, X., Gu, L., Xiao, Y., Gao, Z., Wu, P., Zhang, Y., Meng, X., Wang, J., Zhang, D., Lin, D., Wang, W., & Gu, R. (2019). Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule. Hypertension, 73 (1), 112-120. https://doi.org/10.1161/HYPERTENSIONAHA.118.11621
