Sorting nexin 1 loss results in increased oxidative stress and hypertension.

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D₅ receptor (D₅ 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 (AT₁ R), NADPH oxidase (NOX) subunits, D₅ R, and NaCl cotransporter. Basal reactive oxygen species 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 D₅ R endocytosis, and increased 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 D₅ 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. © 2020 Federation of American Societies for Experimental Biology.

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