Increased AT(1) receptor expression mediates vasoconstriction leading to hypertension in Snx1(-/-) mice

作者全名："Liu, Chao; Li, Xingyue; Fu, Jinjuan; Chen, Ken; Liao, Qiao; Wang, Jialiang; Chen, Caiyu; Luo, Hao; Jose, Pedro A.; Yang, Yongjian; Yang, Jian; Zeng, Chunyu"

作者地址："[Liu, Chao; Li, Xingyue; Fu, Jinjuan; Chen, Ken; Liao, Qiao; Wang, Jialiang; Chen, Caiyu; Luo, Hao; Zeng, Chunyu] Third Mil Med Univ, Daping Hosp, Dept Cardiol, Chongqing, Peoples R China; [Liu, Chao; Fu, Jinjuan; Chen, Ken; Liao, Qiao; Wang, Jialiang; Chen, Caiyu; Luo, Hao; Zeng, Chunyu] Chongqing Inst Cardiol, Chongqing, Peoples R China; [Liu, Chao; Fu, Jinjuan; Chen, Ken; Liao, Qiao; Wang, Jialiang; Chen, Caiyu; Luo, Hao; Zeng, Chunyu] Chongqing Key Lab Hypertens Res, Chongqing, Peoples R China; [Liu, Chao] Nanjing Univ, Jinling Hosp, Sch Med, Dept Emergency Med, Nanjing, Peoples R China; [Li, Xingyue; Yang, Yongjian] Southwest Jiaotong Univ, Coll Med, Chengdu, Sichuan, Peoples R China; [Li, Xingyue; Yang, Yongjian] Gen Hosp Western Theater Command PLA, Dept Cardiovasc Med, Chengdu, Sichuan, Peoples R China; [Jose, Pedro A.] George Washington Univ, Sch Med & Hlth Sci, Div Renal Dis & Hypertens, Washington, DC 20052 USA; [Yang, Jian] Chongqing Med Univ, Dept Clin Nutr, Affiliated Hosp 3, Chongqing, Peoples R China; [Zeng, Chunyu] Third Mil Med Univ, Daping Hosp, State Key Lab Trauma Burns & Combined Injury, Chongqing, Peoples R China; [Zeng, Chunyu] Univ Chinese Acad Sci, Dept Cardiol Chongqing Gen Hosp, Cardiovasc Res Ctr, Chongqing Coll, Chongqing, Peoples R China"

通信作者："Zeng, CY (corresponding author), Third Mil Med Univ, Daping Hosp, Dept Cardiol, Chongqing, Peoples R China.; Zeng, CY (corresponding author), Chongqing Inst Cardiol, Chongqing, Peoples R China.; Zeng, CY (corresponding author), Chongqing Key Lab Hypertens Res, Chongqing, Peoples R China.; Yang, YJ (corresponding author), Southwest Jiaotong Univ, Coll Med, Chengdu, Sichuan, Peoples R China.; Yang, YJ (corresponding author), Gen Hosp Western Theater Command PLA, Dept Cardiovasc Med, Chengdu, Sichuan, Peoples R China.; Yang, J (corresponding author), Chongqing Med Univ, Dept Clin Nutr, Affiliated Hosp 3, Chongqing, Peoples R China.; Zeng, CY (corresponding author), Third Mil Med Univ, Daping Hosp, State Key Lab Trauma Burns & Combined Injury, Chongqing, Peoples R China.; Zeng, CY (corresponding author), Univ Chinese Acad Sci, Dept Cardiol Chongqing Gen Hosp, Cardiovasc Res Ctr, Chongqing Coll, Chongqing, Peoples R China."

来源：HYPERTENSION RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000648814200001

JCR分区：Q1

影响因子：5.4

年份：2021

卷号：44

期号：8

开始页：906

结束页：917

文献类型：Article

关键词：Sorting nexins; Angiotensin II type 1 receptor; Vascular smooth muscle; Blood pressure

摘要："Angiotensin II type 1 receptor (AT(1)R) is a vital therapeutic target for hypertension. Sorting nexin 1 (SNX1) participates in the sorting and trafficking of the renal dopamine D-5 receptor, while angiotensin and dopamine are counterregulatory factors in the regulation of blood pressure. The effect of SNX1 on AT(1)R is not known. We hypothesized that SNX1, through arterial AT(1)R sorting and trafficking, is involved in blood pressure regulation. CRISPR/Cas9 system-generated SNX1(-/-) mice showed dramatic elevations in blood pressure compared to their wild-type littermates. The angiotensin II-mediated contractile reactivity of the mesenteric arteries and AT(1)R expression in the aortas were also increased. Moreover, immunofluorescence and immunoprecipitation analyses revealed that SNX1 and AT(1)R were colocalized and interacted in the aortas of wild-type mice. In vitro studies revealed that AT(1)R protein levels and downstream calcium signaling were upregulated in A10 cells treated with SNX1 siRNA. This may have resulted from decreased AT(1)R protein degradation since the AT(1)R mRNA levels showed no changes. AT(1)R protein was less degraded when SNX1 was downregulated, as reflected by a cycloheximide chase assay. Furthermore, proteasomal rather than lysosomal inhibition increased AT(1)R protein content, and this effect was accompanied by decayed binding of ubiquitin and AT(1)R after SNX1 knockdown. Confocal microscopy revealed that AT(1)R colocalized with PSMD6, a proteasomal marker, and the colocalization was reduced after SNX1 knockdown. These findings suggest that SNX1 sorts AT(1)R for proteasomal degradation and that SNX1 impairment increases arterial AT(1)R expression, leading to increased vasoconstriction and blood pressure."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31730043, 81570379]; National Key R&D Program of China [2018YFC1312700]; National Natural Science FoundationNational Natural Science Foundation of China (NSFC) [81721001]; Program for Changjiang Scholars and Innovative Research Team in UniversityProgram for Changjiang Scholars & Innovative Research Team in University (PCSIRT) [IRT1216]; Third Affiliated Hospital of Chongqing Medical University [KY19024]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-DK039308, P01-HL074940]"

基金资助正文："This study was supported in part by grants from the National Natural Science Foundation of China (31730043, 81570379), the National Key R&D Program of China (2018YFC1312700), the Program of Innovative Research Team by the National Natural Science Foundation (81721001), the Program for Changjiang Scholars and Innovative Research Team in University (IRT1216), The Third Affiliated Hospital of Chongqing Medical University (KY19024), and the National Institutes of Health (R01-DK039308, P01-HL074940)."