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Renal dopamine D2 receptor regulation of the Akt pathway is mediated by PP2A
Author(s) -
zhang yanrong,
yang yu,
asico laureano,
escano crisanto,
yang zhiwei,
Jose pedro A,
Armando ines
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.829.9
Renal dopamine receptors regulate blood pressure, ion transport and cellular functions. This study aimed to determine the role of renal D2 receptors (D2R) in the regulation of protein phosphatase 2A (PP2A) function and the pathways it regulates in the kidney. The expression of PP2Ac (catalytic subunit) and PPP2R2C (regulatory subunit) were decreased in renal cortex of D2−/− mice (18±1 and 20±2%, n=5, P<0.05) and mouse renal proximal tubular cells (mRPTCs) with silenced (siRNA) D2R (60±4 and 55±9 %, n=4, P<0.02). PPP2R2C and D2R colocalized and co‐immunoprecipitated in mRPTCs. PP2A regulates the PI3K‐Akt pathway by dephosphorylating and inactivating Akt. The ratio of phosphorylated Akt (pAkt)/total Akt was increased in renal cortex of D2−/− mice (25±5%, n=5, P<0.05) and in mRPTCs with silenced D2Rs (30±6%, n=4, P<0.05) in which Akt activity was also increased (250±46%, n=5, P<0.02).The mRNA expression of the downstream Akt targets, cyclin D1 (Ccnd1) was increased (1.6 fold, P<0.05) and that of cyclin‐dependent kinase inhibitors 1a (p21) and 2a (p16) was decreased (−2.2 and −6.9 fold respectively, n=4) in renal cortex of D2−/− mice while protein expression of Ccnd was increased in D2R silenced mRPCTs (290±30%, n=4, P<0.02). The silencing of PPP2R2C (siRNA) mirrored the effects of D2R silencing on pAkt and Ccdn1. These results show that D2R regulates renal Akt activity by effects on the activity/expression of PP2A.