Evidence has documented local
angiotensin II (Ang II) as a
pro-oxidant and pro-inflammatory molecule contributes to progressive deterioration of organ function in diseases.
Peroxisome proliferator-activated receptor γ (PPARγ), a
ligand-activated
transcription factor, plays crucial roles in protection against oxidative stress and
inflammation. Ang II stimulation decreases PPARγ
protein in multiple types of cells, while the regulatory role of Ang II on PPARγ is not clear. Here we show that Ang II down-regulated PPARγ in ECV304 cells through 2 actions, inducing nuclear export and loss of
protein. The nuclear export of PPARγ occurred transiently in the early phase, while the reduction in PPARγ
protein happened in the later phase and was more persistent. Both alterations in PPARγ were accompanied by the decrease in PPARγ-
DNA binding activity. Reduction of PPARγ
protein levels was also coupled with the inhibition of PPARγ target genes. In addition, activation of PPARγ by its
ligand troglitazone could completely counteract both 2 actions of Ang II on PPARγ. Further studies demonstrated that the decline of PPARγ
protein was in association with
ubiquitin-
proteasome-dependent degradation, which was supported by the increase in
polyubiquitin-PPARγ conjugates and the inhibitory effect of
lactacystin, a specific
proteasome inhibitor, on the loss of PPARγ. Taken together, this study uncovers a novel means by which Ang II down-regulates PPARγ. This down-regulation disrupts nuclear PPARγ function, which may lead to the loss of beneficial effects of PPARγ in response to Ang II stress.