Abstract 5863: Deficient Dopamine D2 Receptor Function Results in Renal Inflammation and Injury
Alterations in dopamine receptor function have been reported in human and rodent hypertension. Essential hypertension is associated with dopamine D2 receptor (D2R) gene polymorphisms that result in reduced D2R density. Mice with disruption of the D2R (D2-/) have elevated blood pressure. The D2Rs regulate the inflammatory reaction and are implicated in the pathogenesis of inflammatory diseases. We hypothesized that deficient D2R function increases the expression of pro-inflammatory cytokines and chemokines in the kidney and results in renal inflammation and injury that contribute to the development of high blood pressure. To test this hypothesis we determined the renal expression and urinary excretion of inflammatory factors and assessed immune cell infiltration and tissue injury in D2−/− mice and their wild type littermates (D2+/+). Renal expression of TNFα(D2+/+:100±5 vs D2−/−:162±8%, P< 0.05), chemokine ligand 2 (CCL2) (100±10 vs 250±9%, P< 0.02), IL-6 (10035 vs 135±9%, P < 0.05), IL-10 (100±5 vs 173±17%, P < 0.05), determined by western blotting, as well as urinary IL-6 (254±66 vs 729±139 pg/day, P<0.02) and IL-10 (40±18 vs 154±38 pg/day, P<0.02) but not IL-4, determined by ELISA, were increased in D2−/− mice. In contrast VEGF expression was decreased (100±10 vs 58±10%, P<0.05) in D2−/− relative to D2+/+mice. Kidneys from D2−/− mice had clear evidence of glomerulosclerosis, dilation of proximal tubules, tubular proteinaceous casts and interstitial infiltration with inflammatory cells. These lesions were not observed in D2+/+ mice. Urinary albumin was increased in D2−/− relative to D2+/+ mice (94±49 vs13±2 <g/day; P<0.04). Treatment with the anti-oxidant, apocynin (3 mg/k/day × 10 days, via osmotic mini-pump) normalized blood pressure and decreased but did not normalize the renal expression of CCL2 and IL-10, did not affect TNFα and IL-6 expression or urinary excretion, but increased renal VEGF expression. Our results show that the D2R, by mechanisms other than increased oxidant activity, regulates the expression of inflammatory factors in the kidney and suggest that altered D2R function may result in renal inflammation and injury.