PMID- 26290374 OWN - NLM STAT- MEDLINE DCOM- 20160524 LR - 20231111 IS - 1522-1466 (Electronic) IS - 1931-857X (Print) IS - 1522-1466 (Linking) VI - 310 IP - 2 DP - 2016 Jan 15 TI - Dopamine D2 receptors' effects on renal inflammation are mediated by regulation of PP2A function. PG - F128-34 LID - 10.1152/ajprenal.00453.2014 [doi] AB - 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-alpha, monocyte chemoattractant protein-1 (MCP-1), and IL-6. D2R downregulation also increased Akt phosphorylation and activity, and glycogen synthase kinase-3beta (GSK3beta) phosphorylation and cyclin D1 expression, downstream targets of Akt; however. phosphatidylinositol 3-kinase (PI3K) activity was not affected. Conversely, D2R stimulation decreased Akt and GSK3beta 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, GSK3beta, and cyclin D1. The PP2A catalytic subunit and regulatory subunit PPP2R2C coimmunoprecipitated 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 GSK3beta. Moreover, downregulation of PPP2R2C resulted in increased expression of TNF-alpha, 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-kappaB 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. CI - Copyright (c) 2016 the American Physiological Society. FAU - Zhang, Yanrong AU - Zhang Y AD - Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China; and. FAU - Jiang, Xiaoliang AU - Jiang X AD - Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China; and. FAU - Qin, Chuan AU - Qin C AD - Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing, P. R. China; and rinoa2010@126.com. FAU - Cuevas, Santiago AU - Cuevas S AD - Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; FAU - Jose, Pedro A AU - Jose PA AD - Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland. FAU - Armando, Ines AU - Armando I AD - Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; LA - eng GR - R01 DK039308/DK/NIDDK NIH HHS/United States GR - R01DK090918/DK/NIDDK NIH HHS/United States GR - P01HL068686/HL/NHLBI NIH HHS/United States GR - R01 HL092196/HL/NHLBI NIH HHS/United States GR - R01HL092196/HL/NHLBI NIH HHS/United States GR - R37HL023081/HL/NHLBI NIH HHS/United States GR - P01HL074940/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150819 PL - United States TA - Am J Physiol Renal Physiol JT - American journal of physiology. Renal physiology JID - 100901990 RN - 0 (Chemokine CCL2) RN - 0 (Interleukin-6) RN - 0 (NF-kappa B) RN - 0 (Receptors, Dopamine D2) RN - 0 (Tumor Necrosis Factor-alpha) RN - 1W21G5Q4N2 (Okadaic Acid) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 3.1.3.16 (Protein Phosphatase 2) SB - IM MH - Animals MH - Cells, Cultured MH - Chemokine CCL2/metabolism MH - Gene Expression Regulation MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Inflammation/*metabolism MH - Interleukin-6/metabolism MH - Kidney Tubules, Proximal/cytology/drug effects/*metabolism MH - Mice MH - NF-kappa B/metabolism MH - Okadaic Acid/pharmacology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation MH - Protein Phosphatase 2/*metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, Dopamine D2/genetics/*metabolism MH - Signal Transduction/drug effects/*physiology MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC4719046 OTO - NOTNLM OT - AKT OT - dopamine D2 receptor OT - protein phosphatase 1A OT - renal proximal tubule cells EDAT- 2015/08/21 06:00 MHDA- 2016/05/25 06:00 PMCR- 2017/01/15 CRDT- 2015/08/21 06:00 PHST- 2014/08/13 00:00 [received] PHST- 2015/06/15 00:00 [accepted] PHST- 2015/08/21 06:00 [entrez] PHST- 2015/08/21 06:00 [pubmed] PHST- 2016/05/25 06:00 [medline] PHST- 2017/01/15 00:00 [pmc-release] AID - ajprenal.00453.2014 [pii] AID - F-00453-2014 [pii] AID - 10.1152/ajprenal.00453.2014 [doi] PST - ppublish SO - Am J Physiol Renal Physiol. 2016 Jan 15;310(2):F128-34. doi: 10.1152/ajprenal.00453.2014. Epub 2015 Aug 19.