Angiotensin II induces peroxisome proliferator-activated receptor gamma in PC12W cells via angiotensin type 2 receptor activation.
The angiotensin type 2 (AT2) receptor has been previously demonstrated to exert neuroprotective actions possibly by inducing neuronal cell differentiation involving neurite outgrowth. The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is an important transcriptional regulator of cell differentiation. The aim of the present study was to clarify whether PPARgamma is involved in AT2-receptor-mediated morphological neuronal cell differentiation. To investigate AT2-receptor-mediated morphological neuronal cell differentiation, rat pheochromocytoma cells (PC12W cells) expressing AT2 but not AT1 receptors, were stimulated with angiotensin II (Ang II, 100 nmol/L) +/- the PPARgamma antagonists GW9662 (3 micromol/L) and bisphenol A diglycidyl ether (BADGE, 1 micromol/L), and neurite outgrowth of these cells was assessed. Ang II induced neurite outgrowth by 19 +/- 1.6-fold (p < 0.01). Antagonizing PPARgamma activity by GW9662 or BADGE potently blocked Ang II-induced neurite outgrowth (Ang II + GW9662: 6.6 +/- 1.5-fold, p < 0.05; Ang II + BADGE: 1.3 +/- 0.7-fold, p < 0.01). AT2 receptor activation by Ang II markedly induced mRNA and protein expression of the PPARgamma2 isoform and enhanced ligand-induced PPARgamma activity in transactivation assays. In conclusion, the present study demonstrates that Ang II induces PPARgamma expression and ligand-mediated PPARgamma activity via AT2 receptor activation, which appears to be a crucial process in AT2 receptor mediated neurite outgrowth. AT2 receptor/PPARgamma-dependent neurite outgrowth may play an important role during neuroprotective processes.
Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University of Kiel, Kiel, Germany.
Yi
Y
Zhao
Anna
A
Foryst-Ludwig
Dennis
D
Bruemmer
Juraj
J
Culman
Michael
M
Bader
Thomas
T
Unger
Ulrich
U
Kintscher
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D047495:PPAR gamma / Q000096:biosynthesis* / Q000502:physiology; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*
D017306:Annexin A2; D008024:Ligands; D047495:PPAR gamma; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II