{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T11:16:03Z","timestamp":1767870963843,"version":"3.49.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,2,28]]},"abstract":"\n Rationale:<\/jats:title>\n \n Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl\n 1<\/jats:sup>\n -angiotensin II])\u2013elicited AT\n 2<\/jats:sub>\n R (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR).\n <\/jats:p>\n <\/jats:sec>\n \n Objective:<\/jats:title>\n \n This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired AT\n 2<\/jats:sub>\n R signaling and renal sodium (Na\n +<\/jats:sup>\n ) retention by utilizing the selective AT\n 2<\/jats:sub>\n R agonist compound-21 (C-21).\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results:<\/jats:title>\n \n Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic AT\n 1<\/jats:sub>\n R (Ang II type-1 receptor) blockade. Left kidneys received 30-minute renal interstitial infusions of vehicle followed by C-21 (20, 40, and 60 ng\/[kg\u00b7min], each dose 30 minutes). Right kidneys received vehicle infusions. In Wistar Kyoto, C-21 dose-dependently increased urine Na\n +<\/jats:sup>\n excretion from 0.023\u00b10.01 to 0.064\u00b10.02, 0.087\u00b10.01, and 0.089\u00b10.01 \u00b5mol\/min (\n P<\/jats:italic>\n =0.008,\n P<\/jats:italic>\n <0.0001, and\n P<\/jats:italic>\n <0.0001, respectively) and renal interstitial fluid levels of AT\n 2<\/jats:sub>\n R downstream signaling molecule cGMP (cyclic guanosine 3',5' monophosphate) from 0.91\u00b10.3 to 3.1\u00b11.0, 5.9\u00b11.2 and 5.3\u00b10.5 fmol\/mL (\n P<\/jats:italic>\n =nonsignificant,\n P<\/jats:italic>\n <0.0001, and\n P<\/jats:italic>\n <0.0001, respectively). In contrast, C-21 did not increase urine Na\n +<\/jats:sup>\n excretion or renal interstitial cGMP in SHR. Mean arterial pressure was slightly higher in SHR but within the normotensive range and unaffected by C-21. In Wistar Kyoto, but not SHR, C-21 induced AT\n 2<\/jats:sub>\n R translocation to apical plasma membranes of renal proximal tubule cells, internalization\/inactivation of NHE-3 (sodium-hydrogen exchanger-3) and Na\n +<\/jats:sup>\n \/K\n +<\/jats:sup>\n ATPase (sodium-potassium-atpase) and phosphorylation of AT\n 2<\/jats:sub>\n R-cGMP downstream signaling molecules Src (Src family kinase), ERK (extracellular signal-related kinase), and VASP (vasodilator-stimulated phosphoprotein). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-bromo-cGMP. This restored natriuresis, Na\n +<\/jats:sup>\n transporter internalization\/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane AT\n 2<\/jats:sub>\n R recruitment. In contrast, 8-bromo-cAMP administration had no effect on natriuresis or AT\n 2<\/jats:sub>\n R recruitment in SHR.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n The results demonstrate a primary renal proximal tubule cell AT\n 2<\/jats:sub>\n R natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension.\n <\/jats:p>\n <\/jats:sec>\n \n Visual Overview:<\/jats:title>\n An online visual overview is available for this article.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.119.316193","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T13:00:13Z","timestamp":1580389213000},"page":"644-659","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Identification of a Primary Renal AT\n 2<\/sub>\n Receptor Defect in Spontaneously Hypertensive Rats"],"prefix":"10.1161","volume":"126","author":[{"given":"Brandon A.","family":"Kemp","sequence":"first","affiliation":[{"name":"From the Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville (B.A.K., N.L.H., S.R.K., R.M.C.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy L.","family":"Howell","sequence":"additional","affiliation":[{"name":"From the Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville (B.A.K., N.L.H., S.R.K., R.M.C.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.","family":"Gildea","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Virginia Health System, Charlottesville (J.J.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna R.","family":"Keller","sequence":"additional","affiliation":[{"name":"From the Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville (B.A.K., N.L.H., S.R.K., R.M.C.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7238-7396","authenticated-orcid":false,"given":"Robert M.","family":"Carey","sequence":"additional","affiliation":[{"name":"From the Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville (B.A.K., N.L.H., S.R.K., R.M.C.)"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20180121"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01111"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.010454"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000196950.48596.21"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000254833.85106.4d"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.103242"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.191403"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.304110"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.me.31.020180.000311"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(72)90050-2"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.108.124198"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012016"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012644"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308384"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1993.265.5.F736"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00526.2008"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2006"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118273"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.17.9132"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.002907"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2006.09.003"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.110.168708"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.184788"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1043-2760(99)00205-2"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000289"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.06.005"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.00241"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.07.008"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.38.3.309"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.092973"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000112421.18551.1e"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000123574.60586.7d"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000251881.89610.ee"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.194175"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.12705"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01628"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.119.316193","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:01:06Z","timestamp":1715576466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.119.316193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,28]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,2,28]]}},"alternative-id":["10.1161\/CIRCRESAHA.119.316193"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.119.316193","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,28]]},"assertion":[{"value":"2019-10-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}