title: Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries.
abstract: We have reported that the myogenic response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded Hypertensive (FHH) rats. Transfer of a region of chromosome 1 containing γ-adducin (Add3) from the Brown Norway rat rescued the vascular dysfunction and the development of renal disease. To examine whether Add3 is a viable candidate gene altering renal and cerebral hemodynamics in FHH rats, we knocked down the expression of Add3 in rat Af-arts and MCAs cultured for 36-h using a 27-mer Dicer-substrate short interfering RNA (DsiRNA). Control Af-arts constricted by 10 ± 1% in response to an elevation in pressure from 60 to 120 mmHg but dilated by 4 ± 3% when treated with Add3 DsiRNA. Add3 DsiRNA had no effect on the vasoconstrictor response of the Af-art to norepinephrine (10-7M). Add3 DsiRNA had a similar effect on the attenuation of the myogenic response in the MCA. Peak potassium currents were threefold higher in smooth muscle cells isolated from Af-arts or MCAs transfected with Add3 DsiRNA than in nontransfected cells isolated from the same vessels. This is the first study demonstrating that Add3 plays a role in the regulation of potassium channel function and vascular reactivity. It supports the hypothesis that sequence variants in Add3, which we previously identified in FHH rats, may play a causal role in the impaired myogenic response and autoregulation in the renal and cerebral circulation.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Pabbidi
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Longyang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Shaoxun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Paige N
authors.initials: PN
authors.lastname: Mims
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi rroman@umc.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D008564:Membrane Potentials; D020768:Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D011188:Potassium / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D046509:Tissue Culture Techniques; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; D011188:Potassium; D014662:Vasoconstrictor Agents; C000621747:Add3 protein, rat; D000099291:Adducins
keywords: Add3; brain; kidney; myogenic response; vascular smooth muscle cell