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

Document Type

Journal Article

Publication Date

1-15-2016

Journal

American Journal of Physiology - Renal Physiology

Volume

310

Issue

2

DOI

10.1152/ajprenal.00453.2014

Keywords

AKT; Dopamine D receptor 2; Protein phosphatase 1A; Renal proximal tubule cells

Abstract

© 2016 the American Physiological Society. Lack or downregulation of the dopamine D2 receptor (D2R) results in increased renal expression of injury markers and proinflammatory factors that is independent of a 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 proinflammatory TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6. D2R downregulation also increased Akt phosphorylation and activity, and glycogen synthase kinase-3β (GSKβ3) phosphorylation and cyclin D1 expression, downstream targets of Akt; however. phosphatidylinositol 3-kinase (PI3K) activity was not affected. Conversely, D2R stimulation decreased Akt and GSKβ3 phosphorylation and cyclin D1 expression. Increased phospho-Akt, in the absence of increased PI3K activity, may result from decreased Akt dephosphorylation. Inhibition of protein phosphatase 2A (PP2A) with okadaic acid reproduced the effects of D2R downregulation on Akt, GSKβ3, and cyclin D1. The PP2A catalytic subunit and regulatory subunit PPP2R2C coimmunoprecipi- tated 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 GSK3 . Moreover, downregulation of PPP2R2C resulted in increased expression of TNF-, MCP-1, and IL-6, indicating that decreased phosphatase activity may be responsible for the D2R effect on inflammatory factors. Indeed, the increase in NF- B 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.

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