title: Angiotensin II type 2 receptor regulates ROMK-like K⁺ channel activity in the renal cortical collecting duct during high dietary K⁺ adaptation.
abstract: The kidney adjusts K⁺ excretion to match intake in part by regulation of the activity of apical K⁺ secretory channels, including renal outer medullary K⁺ (ROMK)-like K⁺ channels, in the cortical collecting duct (CCD). ANG II inhibits ROMK channels via the ANG II type 1 receptor (AT1R) during dietary K⁺ restriction. Because AT1Rs and ANG II type 2 receptors (AT2Rs) generally function in an antagonistic manner, we sought to characterize the regulation of ROMK channels by the AT2R. Patch-clamp experiments revealed that ANG II increased ROMK channel activity in CCDs isolated from high-K⁺ (HK)-fed but not normal K⁺ (NK)-fed rats. This response was blocked by PD-123319, an AT2R antagonist, but not by losartan, an AT1R antagonist, and was mimicked by the AT2R agonist CGP-42112. Nitric oxide (NO) synthase is present in CCD cells that express ROMK channels. Blockade of NO synthase with N-nitro-l-arginine methyl ester and free NO with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt completely abolished ANG II-stimulated ROMK channel activity. NO enhances the synthesis of cGMP, which inhibits phosphodiesterases (PDEs) that normally degrade cAMP; cAMP increases ROMK channel activity. Pretreatment of CCDs with IBMX, a broad-spectrum PDE inhibitor, or cilostamide, a PDE3 inhibitor, abolished the stimulatory effect of ANG II on ROMK channels. Furthermore, PKA inhibitor peptide, but not an activator of the exchange protein directly activated by cAMP (Epac), also prevented the stimulatory effect of ANG II. We conclude that ANG II acts at the AT2R to stimulate ROMK channel activity in CCDs from HK-fed rats, a response opposite to that mediated by the AT1R in dietary K⁺-restricted animals, via a NO/cGMP pathway linked to a cAMP-PKA pathway.
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacology, New York Medical College, Valhalla, New York; Department of Cell Biology, New York University Medical Center, New York, New York yuan.wei@nyumc.org.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Cell Biology, New York University Medical Center, New York, New York.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Beth
authors.initials: B
authors.lastname: Zavilowitz
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Pokman
authors.initials: P
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, James J. Peters Veterans Affairs Medical Center, Bronx, New York; and.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Rohatgi
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Genevieve
authors.initials: G
authors.lastname: Estilo
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Satlin
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D005260:Female; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D017419:Potassium, Dietary / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D017419:Potassium, Dietary; D044139:Receptor, Angiotensin, Type 2
keywords: angiotensin II; angiotensin II type 2 receptor; cortical collecting duct; protein kinase A; renal outer medullary potassium channel
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