期刊
FASEB JOURNAL
卷 34, 期 6, 页码 7941-7957出版社
WILEY
DOI: 10.1096/fj.201902448R
关键词
dopamine D-5 receptor; hypertension; oxidative stress; renal proximal tubule cells; sorting nexin 1
资金
- National Institutes of Health [R37-HL023081, R01-DK039308, R01-HL092196, R01-DK090918, P01-HL068686, 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]
- Research Service of the Department of Veterans Affairs
- Norma E. Clauss Clinical Research Award by the National Institutes of Health Pharmacogenetics Research Network grant [U01-GM074492]
- National Center for Advancing Translational Sciences [UL1-TR000064, UL1-TR000454, UL1-TR000135]
- Mayo Foundation
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.
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