@article{f954c7d34ce14d38a021508bfac1d7b9,
title = "Sorting nexin 1 loss results in increased oxidative stress and hypertension",
abstract = "Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.",
keywords = "dopamine D receptor, hypertension, oxidative stress, renal proximal tubule cells, sorting nexin 1",
author = "Jian Yang and Asico, {Laureano D.} and Beitelshees, {Amber L.} and Feranil, {Jun B.} and Xiaoyan Wang and Jones, {John E.} and Ines Armando and Cuevas, {Santiago G.} and Schwartz, {Gary L.} and Gums, {John G.} and Chapman, {Arlene B.} and Turner, {Stephen T.} and Eric Boerwinkle and Cooper-DeHoff, {Rhonda M.} and Johnson, {Julie A.} and Felder, {Robin A.} and Weinman, {Edward J.} and Chunyu Zeng and Jose, {Pedro A.} and Villar, {Van Anthony M.}",
note = "Funding Information: We would like to acknowledge the help of Yen‐Pei Chang, PhD, from the Departments of Medicine and Epidemiology & Public Health, and James A. Perry, PhD, from the Department of Medicine, University of Maryland School of Medicine for their assistance in the data analysis. This work was supported by the following grants: National Institutes of Health (R37‐HL023081, R01‐DK039308, R01‐HL092196, R01‐DK090918, P01‐HL068686, and P01‐HL074940), National Natural Science Foundation of China (81570379, 81770425), Natural Science Foundation Project of Chongqing (cstc2015jcyjA10060), Key Program of The Third Affiliated Hospital of Chongqing Medical University (KY19024), DK‐5581 and funds from the Research Service of the Department of Veterans Affairs, and the Norma E. Clauss Clinical Research Award given to VAV by the National Kidney Foundation of Maryland. PEAR is supported by the National Institutes of Health Pharmacogenetics Research Network grant U01‐GM074492 and the National Center for Advancing Translational Sciences under the award number UL1‐TR000064 (University of Florida); UL1‐TR000454 (Emory University) and UL1‐TR000135 (Mayo Clinic) and funds from the Mayo Foundation. We are deeply saddened by the sudden loss of Dr Van Anthony M. Villar, and will keep him in our memories. Funding Information: We would like to acknowledge the help of Yen-Pei Chang, PhD, from the Departments of Medicine and Epidemiology & Public Health, and James A. Perry, PhD, from the Department of Medicine, University of Maryland School of Medicine for their assistance in the data analysis. This work was supported by the following grants: National Institutes of Health (R37-HL023081, R01-DK039308, R01-HL092196, R01-DK090918, P01-HL068686, and P01-HL074940), National Natural Science Foundation of China (81570379, 81770425), Natural Science Foundation Project of Chongqing (cstc2015jcyjA10060), Key Program of The Third Affiliated Hospital of Chongqing Medical University (KY19024), DK-5581 and funds from the Research Service of the Department of Veterans Affairs, and the Norma E. Clauss Clinical Research Award given to VAV by the National Kidney Foundation of Maryland. PEAR is supported by the National Institutes of Health Pharmacogenetics Research Network grant U01-GM074492 and the National Center for Advancing Translational Sciences under the award number UL1-TR000064 (University of Florida); UL1-TR000454 (Emory University) and UL1-TR000135 (Mayo Clinic) and funds from the Mayo Foundation. We are deeply saddened by the sudden loss of Dr Van Anthony M. Villar, and will keep him in our memories. Publisher Copyright: {\textcopyright} 2020 Federation of American Societies for Experimental Biology",
year = "2020",
month = jun,
day = "1",
doi = "10.1096/fj.201902448R",
language = "English (US)",
volume = "34",
pages = "7941--7957",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "6",
}