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

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2019-01, Vol.73 (1), p.112-120
• Main Authors: Duan, Xin-Peng, Gu, Li, Xiao, Yu, Gao, Zhong-Xiuzi, Wu, Peng, Zhang, Yun-Hong, Meng, Xin-Xin, Wang, Jun-Lin, Zhang, Dan-Dan, Lin, Dao-Hong, Wang, Wen-Hui, Gu, Ruimin
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists - pharmacology; Animals; Ion Transport - drug effects; Ion Transport - physiology; Isoproterenol - pharmacology; Kidney Tubules, Distal - drug effects; Kidney Tubules, Distal - metabolism; Kir5.1 Channel; Mice; Mice, Knockout; Norepinephrine - metabolism; Potassium Channels, Inwardly Rectifying - metabolism; Propranolol - pharmacology; Receptors, Adrenergic, beta - metabolism; Solute Carrier Family 12, Member 1 - metabolism; Solute Carrier Family 12, Member 3 - metabolism
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.118.11621

The stimulation of β–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 β–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 α–adrenergic agonist and blocked by propranolol, suggesting that norepinephrine effect on the K channel was mediated by β–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-α (epithelial Na channel-α 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 β–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.