title: Sestrin2 decreases renal oxidative stress, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of reactive oxygen species production.
abstract: The dopamine D2 receptor (D2R) decreases renal reactive oxygen species (ROS) production and regulates blood pressure, in part, via positive regulation of paraoxonase 2. Sestrin2, a highly conserved antioxidant protein, regulates intracellular ROS level by regenerating hyperoxidized peroxiredoxins. We hypothesized that sestrin2 may be involved in preventing excessive renal ROS production and thus contribute to the maintenance of normal blood pressure. Moreover, the D2R may decrease ROS production, in part, through the regulation of sestrin2. Renal sestrin2 expression was lower (-62±13%) in D2R(-/-) than in D2R(+/+) mice. Silencing D2R in human renal proximal tubule cells decreased sestrin2 expression (-53±3%) and increased hyperoxidized peroxiredoxins (2.9-fold). Stimulation of D2R in renal proximal tubule cells increased sestrin2 expression (1.6-fold), decreased hyperoxidized peroxiredoxins (-61±3%), and reduced ROS production (-31±4%). Silencing sestrin2 in renal proximal tubule cells increased hyperoxidized peroxiredoxins (2.1-fold) and ROS production (1.3-fold). Silencing sestrin2 also abolished D2R-induced decrease in peroxiredoxin hyperoxidation and partially prevented the inhibitory effect of D2R stimulation on ROS production. Silencing paraoxonase 2 increased sestrin2 ubiquitinylation (2.8-fold), decreased sestrin2 expression (-30±3%), and increased ROS production (1.3-fold), peroxiredoxin hyperoxidation (2.9-fold), and lipid peroxidation (2.3-fold), and blocked the increase in sestrin2 that occurs with D2R stimulation. In vivo renal selective silencing of sestrin2 by the renal subcapsular infusion of sestrin2 small interfering RNA (3 μg/day; 7 days) in mice increased renal oxidative stress (1.3-fold) and blood pressure. These results suggest that the D2R, via paraoxonase 2 and sestrin2, keeps normal renal redox balance, which contributes to the maintenance of normal blood pressure.
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore. yyang@medicine.umaryland.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Santiago
authors.initials: S
authors.lastname: Cuevas
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Sufei
authors.initials: S
authors.lastname: Yang
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Van Anthony
authors.initials: VA
authors.lastname: Villar
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Crisanto
authors.initials: C
authors.lastname: Escano
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Laureano
authors.initials: L
authors.lastname: Asico
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Peiying
authors.initials: P
authors.lastname: Yu
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Weinman
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.affiliation: From the Division of Nephrology and Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010544:Peroxidases; D054464:Peroxiredoxins / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000084622:Sestrins
chemical_list: D043303:Aryldialkylphosphatase; D018491:Dopamine Agonists; D009687:Nuclear Proteins; D010544:Peroxidases; D054464:Peroxiredoxins; D019257:Quinpirole; D017382:Reactive Oxygen Species; D017448:Receptors, Dopamine D2; C465398:SESN2 protein, human; D000084622:Sestrins; C529380:Sesn2 protein, mouse; C468411:PON2 protein, human
keywords: aryldialkylphosphatase; hypertension; peroxiredoxins; reactive oxygen species; receptors, dopamine D2