title: Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension.
abstract: Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. Although both hemodynamic and tubular effects likely participate, most evidence supports a major role for α-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive NaCl cotransporter (NCC) by stimulating β-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on β-adrenergic receptors. This effect is not mediated by the activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule to show that distal convoluted tubule cells are especially enriched for β₁-adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. Because the 2 protein kinases, STE20p-related proline- and alanine-rich kinase (encoded by STK39) and oxidative stress-response kinase 1, phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect STE20p-related proline- and alanine-rich kinase abundance or its localization in the distal convoluted tubule; instead, we observed a striking activation of oxidative stress-response kinase 1. We confirmed that STE20p-related proline- and alanine-rich kinase is not required for NCC activation, using STK39 knockout mice. Together, the data provide strong support for a signaling system involving β₁-receptors in the distal convoluted tubule that activates NCC, at least in part via oxidative stress-response kinase 1. The results have implications about device- and drug-based treatment of hypertension.
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: James A
authors.initials: JA
authors.lastname: McCormick
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Meermeier
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Shaunessy L
authors.initials: SL
authors.lastname: Rogers
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Solveig
authors.initials: S
authors.lastname: Grossmann
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Katja
authors.initials: K
authors.lastname: Trompf
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland (A.S.T., C.-L.Y., J.A.M., N.P.M., S.L.R., D.H.E.); Renal Section, VA Medical Center, Portland, OR (C.-L.Y., N.P.M., D.H.E.); Institute of Anatomy, University of Zurich, Zurich, Switzerland (S.G., K.T., J.L.); and Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN (E.D.). ellisond@ohsu.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018342:Receptors, Adrenergic, beta-1; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; D009638:Norepinephrine
keywords: diuretics; hypertension; ion transport; sodium-potassium-chloride symporters; sympathetic nervous system