Sorting nexin 1 loss results in increased oxidative stress and hypertension
Open Access
- 1 June 2020
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 34 (6), 7941-7957
- https://doi.org/10.1096/fj.201902448R
Abstract
Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D-5 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 (AT(1)R), 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.Funding Information
- National Institutes of Health (R37‐HL023081, R01‐DK039308, R01‐HL092196, R01‐DK090918, P01‐HL068686, P01‐HL074940, U01‐GM074492)
- National Natural Science Foundation of China (81570379, 81770425)
- U.S. Department of Veterans Affairs
- National Kidney Foundation
- National Center for Advancing Translational Sciences (UL1‐TR000064, UL1‐TR000454, UL1‐TR000135)
- Mayo Foundation for Medical Education and Research
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