title: Heterozygous disruption of renal outer medullary potassium channel in rats is associated with reduced blood pressure.
abstract: The renal outer medullary potassium channel (ROMK, KCNJ1) mediates potassium recycling and facilitates sodium reabsorption through the Na(+)/K(+)/2Cl(-) cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Human genetic studies indicate that ROMK homozygous loss-of-function mutations cause type II Bartter syndrome, featuring polyuria, renal salt wasting, and hypotension; humans heterozygous for ROMK mutations identified in the Framingham Heart Study have reduced blood pressure. ROMK null mice recapitulate many of the features of type II Bartter syndrome. We have generated an ROMK knockout rat model in Dahl salt-sensitive background by using zinc finger nuclease technology and investigated the effects of knocking out ROMK on systemic and renal hemodynamics and kidney histology in the Dahl salt-sensitive rats. The ROMK(-/-) pups recapitulated features identified in the ROMK null mice. The ROMK(+/-) rats, when challenged with a 4% salt diet, exhibited a reduced blood pressure compared with their ROMK(+/+) littermates. More importantly, when challenged with an 8% salt diet, the Dahl salt-sensitive rats with 50% less ROMK expression showed increased protection from salt-induced blood pressure elevation and signs of protection from renal injury. Our findings in ROMK knockout Dahl salt-sensitive rats, together with the previous reports in humans and mice, underscore a critical role of ROMK in blood pressure regulation.
authors.affiliation: Department of Cardiovascular Diseases, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065, USA. xiaoyan_zhou@merck.com
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.forename: Zuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Myung Kyun
authors.initials: MK
authors.lastname: Shin
authors.forename: Sarah Beth
authors.initials: SB
authors.lastname: Horwitz
authors.forename: John M
authors.initials: JM
authors.lastname: Levorse
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Wanda
authors.initials: W
authors.lastname: Sharif-Rodriguez
authors.forename: Denis Y
authors.initials: DY
authors.lastname: Streltsov
authors.forename: Maya
authors.initials: M
authors.lastname: Dajee
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Olga
authors.initials: O
authors.lastname: Urosevic-Price
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.forename: Daphne
authors.initials: D
authors.lastname: Szeto
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.forename: Bindhu
authors.initials: B
authors.lastname: Michael
authors.forename: Leslie Ann
authors.initials: LA
authors.lastname: Balogh
authors.forename: Paul A
authors.initials: PA
authors.lastname: Welling
authors.forename: James B
authors.initials: JB
authors.lastname: Wade
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D001794:Blood Pressure; D005260:Female; D006579:Heterozygote; D007668:Kidney / Q000502:physiology; D008297:Male; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology*; D051381:Rats; D020303:Rats, Inbred Dahl; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology; D064466:Solute Carrier Family 12, Member 1
chemical_list: C510692:Kcnj1 protein, rat; D024661:Potassium Channels, Inwardly Rectifying; C578714:SLC12A1 protein, human; C578715:Slc12a1 protein, mouse; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1
keywords: Dahl salt-resistant rats; Kcnj1 protein, rat; ROMK protein, rat; gene knockout; hypertension; renal insufficiency, acute