Dopamine D2 receptors effects on renal inflammation are mediated by regulation of PP2A function.

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 mod...

Source: Am J Physiol Renal P... - August 19, 2015 Category: Urology & Nephrology Authors: Zhang Y, Jiang X, Qin C, Cuevas S, Jose PA, Armando I Tags: Am J Physiol Renal Physiol Source Type: research