Lack or downregulation of the dopamine D2 receptor (D₂R) results in increased renal expression of injury markers and pro-inflammatory factors that is independent of blood pressure increase. This study aimed to determine the mechanisms involved in the regulation of renal inflammation by D₂Rs. Silencing D₂Rs in mouse renal proximal tubule cells increased the expression of the pro-inflammatory TNFα, MCP-1, and IL-6. D₂R downregulation also increased Akt phosphorylation and activity, and GSK3β phosphorylation and cyclin D1 expression both downstream Akt targets, however PI3K activity was not affected. Conversely D₂R stimulation decreased Akt and GSK3β phosphorylation and cyclin D1 expression. Increased phospho-Akt, in the absence of increased PI3K activity, may result from decreased Akt dephosphorylation. Inhibition of PP2A with okadaic acid reproduced the effects of D₂R downregulation on Akt, GSK3β and cyclin D1. PP2A catalytic subunit and the regulatory subunit PPP2R2C co-immunoprecipitated with the D₂R. Basal phosphatase activity and the expression of PPP2R2C were decreased by D₂R silencing that also blunted the increase in phosphatase activity induced by D₂R stimulation. Similarly, silencing PPP2R2C also increased the phosphorylation of Akt and GSK3β. Moreover, downregulation of PPP2R2C resulted in increased expression of TNFα, MCP-1, and IL-6, indicating that decreased phosphatase activity may be responsible for the D₂R effect on inflammatory factors. Indeed, the increase in NFkB reporter activity induced by D₂R silencing was blunted by increasing PP2A activity with protamine. Our results show that D₂R controls renal inflammation, at least in part, by modulation of the Akt pathway through effects on PP2A activity/expression.