The lack of dopamine D2 receptor (D2R) function in one or both kidneys in mice increases blood pressure (BP) and vulnerability to renal inflammation. D2R downregulation in only one kidney by the unilateral renal subcapsular infusion of D2R siRNA (3µg/day; 28 days) in mice increased systolic BP (Pre-infusion: 99 ± 3; Post-infusion: 125 ± 2 mmHg; n=5, P<0.02) while non-silencing siRNA did not (Pre: 100 ± 2; Post: 103 ± 3; n=5). The expression of TNFα, TNFβ, MCP-1, IL-6 and the injury markers Lcn2, Fn1 and Col1a were increased only in the D2R siRNA-infused kidney. To study the involvement of renal nerves in the BP increase in this model we performed renal denervation at the start of the mock or D2R-siRNA infusion and BP and inflammatory and renal injury markers were measured on day 28. The increase in BP in response to D2R-siRNA infusion in one kidney was similar in mice with intact innervation in both kidneys, denervation of the non-infused kidney, denervation of the D2R-siRNA-infused kidney, or denervation of both kidneys, indicating that renal nerves do not contribute to the increase in BP with decreased D2R function in one kidney. Denervation of the non-infused kidney blunted while denervation of the siRNA-infused kidney enhanced the increase in TNFα, Fn1, and Col1a expression, indicating that renal nerves restrain the inflammatory response. These results show a protective role of the D2R on renal inflammation and development of hypertension. Renal innervation modulates the expression of inflammatory and renal injury markers but does not affect BP in this model.