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Involvement of AKT/FOXO Genes in the Interactions of PPARα and PHD in DOCA‐Induced Pathology
Author(s) -
CHOI MYUNG,
OYEKAN ADEBAYO
Publication year - 2019
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.2019.33.1_supplement.749.2
Subject(s) - foxo1 , endocrinology , medicine , fibrosis , clofibrate , peroxisome proliferator activated receptor , inflammation , receptor , downregulation and upregulation , chemistry , protein kinase b , signal transduction , cancer research , gene , biochemistry
Prolyl hydroxylase (PHD) and peroxisome proliferator activated receptor (PPAR)α, known “sensors” of cellular energy and/or oxygen and have been demonstrated to mitigate against oxidative stress, inflammation and fibrosis in cardiorenal pathologies. However, it is not fully known if any commonality exists in their mechanisms of action. This study evaluated the role of Akt/Forkhead box protein FOXO pathway as a possible common target for both PHD and PPARα. In uninephrectomized rats treated with DOCA and 1% NaCl, hypertension was accompanied by cardiac/renal hypertrophy (P<0.05) and marked proteinuria (P<0.01). Accompanying these effects were increases in the expression of TGFβ (72±14%), a marker of fibrosis, p65 (60±7%), an index of inflammation, pAkt (82±10%), a key signaling protein in cellular function, and PHD2 (90±8%), an index of hypoxia but reduced expression of FOXO1 (27±4%) and PPARα (27±6%). Clofibrate, a PPARα ligand, attenuated the hypertension (P<0.05), organ hypertrophy and proteinuria (P<0.05) and blunted the expression of PHD2 (45±6%, P<0.05), pAKt (66±4%, P<0.05), TGFb (P<0.05) and p65 (P<0.05) without changes in MnSOD expression. Combined administration of clofibrate and DMOG, the inhibitor of PHD, exacerbated these effects. These data suggest that FOXO proteins may compliment the activities of PPARα. Moreover, PPARα activation and PHD2 inhibition resulted in similar signaling mechanisms and that combined PPARα activation and PHD2 inhibition may constitute a more effective therapeutic approach in the management of hypertension. Support or Funding Information National Institutes of Health grant G12MD007605 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .