Sorting nexin 1 loss results in increased oxidative stress and hypertension.
Sorting nexin 1 loss results in increased oxidative stress and hypertension.
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分选 nexin 1 损失导致氧化应激和高血压增加
DOI：
10.1096/fj.201902448r
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发表时间：
2020-06
期刊：
影响因子：
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通讯作者：
Villar VAM
中科院分区：
文献类型：
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作者：
Yang J;Asico LD;Beitelshees AL;Feranil JB;Wang X;Jones JE;Armando I;Cuevas SG;Schwartz GL;Gums JG;Chapman AB;Turner ST;Boerwinkle E;Cooper-DeHoff RM;Johnson JA;Felder RA;Weinman EJ;Zeng C;Jose PA;Villar VAM
小鼠中的分选连接蛋白1（SNX 1）的急性肾耗竭导致由于多巴胺D5受体（D5 R）活性受损而导致的利钠反应减弱和高血压。我们阐明了Snx 1 −/−小鼠中这些表型的分子机制。这些小鼠肾脏血管紧张素II 1型受体（AT 1 R）、NADPH氧化酶（NOX）亚单位、D5 R和NaCl协同转运蛋白的表达增加。Snx 1 −/−小鼠的基础活性氧（ROS）、NOX活性和血压（BP）也较高，这些都是通过apocynin（一种阻止NOX组装的药物）正常化的。高血压（HT）欧美男性的肾近端小管（RPT）细胞与血压正常（NT）欧美男性的细胞相比，SNX 1活性不足，D5 R内吞受损，ROS增加。siRNA介导的NT受试者RPT细胞中SNX 1的耗竭导致D5 R激动剂诱导的cAMP产生增加和Na+转运减少的钝化，这些效应通过SNX 1的过度表达而正常化。在HT非裔美国人中，SNX 1基因的12个单核苷酸多态性中有3个与氢氯噻嗪（HCTZ）引起的收缩压降低相关。这些结果为高血压的发展提供了一个新的范例，并暗示运输蛋白SNX 1可能是高血压和抗高血压治疗反应的关键决定因素。
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.