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Keywords:

  • angiotensin II;
  • angiotensin receptors;
  • cell differentiation;
  • neuroprotection;
  • peroxisome proliferator-activated receptor gamma

Abstract

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 (PPARγ) is an important transcriptional regulator of cell differentiation. The aim of the present study was to clarify whether PPARγ 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 PPARγ antagonists GW9662 (3 µmol/L) and bisphenol A diglycidyl ether (BADGE, 1 µmol/L), and neurite outgrowth of these cells was assessed. Ang II induced neurite outgrowth by 19 ± 1.6-fold (p < 0.01). Antagonizing PPARγ 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 PPARγ2 isoform and enhanced ligand-induced PPARγ activity in transactivation assays. In conclusion, the present study demonstrates that Ang II induces PPARγ expression and ligand-mediated PPARγ activity via AT2 receptor activation, which appears to be a crucial process in AT2 receptor mediated neurite outgrowth. AT2 receptor/PPARγ-dependent neurite outgrowth may play an important role during neuroprotective processes.