Adenosine A3 Receptors Regulate Oxidative Stress and Inflammatory Responses in A Model of Hypertension and Renal Disease

BACKGROUND: Adenosine A1 and A2 receptors are known to regulate renal autoregulation and blood pressure, but the role of A3 signaling is unknown. We previously demonstrated early life reduction in nephron number (UNX) combined with high salt diet (HS) induced renal oxidative stress and hypertension in rats. This study aimed at investigating the role of A3 receptor in modulating renal and cardiovascular function in this disease model. METHODS: Wild-type (WT) and A3 knockout (A3KO) mice underwent UNX or sham-operation at 3-week-age followed by HS treatment. Blood pressure and renal function were measured in conscious aged mice and renal oxidative stress as well as inflammatory properties was characterized. RESULTS: WT but not A3KO with UNX+HS developed hypertension and cardiac hypertrophy (WT: 4.5±0.1 vs 4.0±0.1; A3KO: 4.7±0.2 vs 4.6±0.1 mg/gBW), characterized by impaired renal plasma flow (RPF), glomerular hyperfiltration and increased renal NADPH oxidase activity (Fig. 1A-C). UNX+HS increased plasma IL-6 (36.1±5.7 vs 16.3±2.4 pg/ml) and IL-10 (37.8±3.9 vs 25.4±2.4 pg/ml) levels in WT, but not in A3KO (39.7±3.9 vs 38.5±5.9 pg/ml and 46.5±3.7 vs 43.9±6.0 pg/ml respectively). However, A3KO displayed higher baseline cytokine levels. Furthermore, bone marrow-derived macrophages from A3KO mice expressed higher M1 (PDL-1 and CD86) and M2 (PDL2 and CD206) markers under LPS stimulation compared with WT. These suggested an enhanced innate immune response in A3KO. CONCLUSION: UNX followed by HS intake lead to renal and cardiovascular dysfunction, which importantly depends on A3 receptor-mediated regulation of oxidative stress and inflammation.