{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:24:17Z","timestamp":1785763457027,"version":"3.56.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,7,6]]},"abstract":"\n Background<\/jats:title>\n \n Early\u2010life reduction in nephron number (uninephrectomy [\n UNX]<\/jats:styled-content>\n ) and chronic high salt (\n HS<\/jats:styled-content>\n ) intake increase the risk of hypertension and chronic kidney disease. Adenosine signaling via its different receptors has been implicated in modulating renal, cardiovascular, and metabolic functions as well as inflammatory processes; however, the specific role of the A\n 3<\/jats:sub>\n receptor in cardiovascular diseases is not clear. In this study, gene\u2010modified mice were used to investigate the hypothesis that lack of A\n 3<\/jats:sub>\n signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (\n UNX<\/jats:styled-content>\n \u2010\n HS<\/jats:styled-content>\n ) in mice.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Wild\u2010type (A\n 3<\/jats:sub>\n +\/+<\/jats:sup>\n ) mice subjected to\n UNX<\/jats:styled-content>\n \u2010\n HS<\/jats:styled-content>\n developed hypertension compared with controls (mean arterial pressure 106\u00b13 versus 82\u00b13\u00a0mm\u00a0Hg;\n P<\/jats:italic>\n <0.05) and displayed an impaired metabolic phenotype (eg, increased adiposity, reduced glucose tolerance, hyperinsulinemia). These changes were associated with both cardiac hypertrophy and fibrosis together with renal injuries and proteinuria. All of these pathological hallmarks were significantly attenuated in the A\n 3<\/jats:sub>\n \u2212\/\u2212<\/jats:sup>\n mice. Mechanistically, absence of A\n 3<\/jats:sub>\n receptors protected from\n UNX<\/jats:styled-content>\n \u2010\n HS<\/jats:styled-content>\n \u2013associated increase in renal\n NADPH<\/jats:styled-content>\n oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1\u03b2, 6, 12, and 10 were increased in A\n 3<\/jats:sub>\n +\/+<\/jats:sup>\n following\n UNX<\/jats:styled-content>\n \u2010\n HS<\/jats:styled-content>\n , but these cytokines were already elevated in na\u00efve A\n 3<\/jats:sub>\n \u2212\/\u2212<\/jats:sup>\n mice and did not change following\n UNX<\/jats:styled-content>\n \u2010\n HS<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Reduction in nephron number combined with chronic\n HS<\/jats:styled-content>\n intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A\n 3<\/jats:sub>\n receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.116.003868","type":"journal-article","created":{"date-parts":[[2016,7,19]],"date-time":"2016-07-19T03:08:33Z","timestamp":1468897713000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":30,"title":["Genetic Abrogation of Adenosine A\n 3<\/sub>\n Receptor Prevents Uninephrectomy and High Salt\u2013Induced Hypertension"],"prefix":"10.1161","volume":"5","author":[{"given":"Ting","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa","family":"Zollbrecht","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malin E.","family":"Winerdal","sequence":"additional","affiliation":[{"name":"Unit of Translational Immunology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengbing","family":"Zhuge","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing\u2010Mei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niccolo","family":"Terrando","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Checa","sequence":"additional","affiliation":[{"name":"Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"S\u00e4llstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig E.","family":"Wheelock","sequence":"additional","affiliation":[{"name":"Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola","family":"Winqvist","sequence":"additional","affiliation":[{"name":"Unit of Translational Immunology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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