Premium
Sorting nexin 1 loss results in increased oxidative stress and hypertension
Author(s) -
Yang Jian,
Asico Laureano D.,
Beitelshees Amber L.,
Feranil Jun B.,
Wang Xiaoyan,
Jones John E.,
Armando Ines,
Cuevas Santiago G.,
Schwartz Gary L.,
Gums John G.,
Chapman Arlene B.,
Turner Stephen T.,
Boerwinkle Eric,
CooperDeHoff Rhonda M.,
Johnson Julie A.,
Felder Robin A.,
Weinman Edward J.,
Zeng Chunyu,
Jose Pedro A.,
Villar Van Anthony M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902448r
Subject(s) - medicine , endocrinology , nadph oxidase , nox4 , apocynin , chemistry , p22phox , sorting nexin , fenoldopam , oxidative stress , receptor , agonist , biology , endosome
Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D 5 receptor (D 5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1 −/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT 1 R), NADPH oxidase (NOX) subunits, D 5 R, 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 D 5 R 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 D 5 R 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.