Genetic Abrogation of Adenosine A3 Receptor Prevents Uninephrectomy and High Salt–Induced Hypertension
Background Early‐life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) 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...
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Published in | Journal of the American Heart Association Vol. 5; no. 7 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
John Wiley and Sons Inc
18.07.2016
Wiley |
Subjects | |
Online Access | Get full text |
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Summary: | Background
Early‐life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) 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 A3 receptor in cardiovascular diseases is not clear. In this study, gene‐modified mice were used to investigate the hypothesis that lack of A3 signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (UNX‐HS) in mice.
Methods and Results
Wild‐type (A3+/+) mice subjected to UNX‐HS developed hypertension compared with controls (mean arterial pressure 106±3 versus 82±3 mm Hg; P<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 A3−/− mice. Mechanistically, absence of A3 receptors protected from UNX‐HS–associated increase in renal NADPH oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1β, 6, 12, and 10 were increased in A3+/+ following UNX‐HS, but these cytokines were already elevated in naïve A3−/− mice and did not change following UNX‐HS.
Conclusions
Reduction in nephron number combined with chronic HS intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A3 receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Dr Yang is currently located at the Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC. Dr Terrando is currently located at the Department of Anesthesiology, Duke University Medical Center, Durham, NC. |
ISSN: | 2047-9980 2047-9980 |
DOI: | 10.1161/JAHA.116.003868 |