Angiotensin (1–7) Antagonizes Angiotensin II Action in SHR Hypothalamic Neurons via Stimulation of PTEN Expression

Abstract

It was demonstrated previously that Ang (1–7) counter‐regulates Ang II action in neuronal activity of SHR neurons. However, the underlying molecular mechanisms are still not fully known. Our objective in the present study was to characterize the signal transduction mechanism of phosphatidylinositol 3‐kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN) involvement in the counter‐regulatory effect of Ang (1–7) on Ang II action in neurons cultured from hypothalamus of WKY vs. SH rats using current clamp recording.Application of Ang II produced a 44% greater increase in neuronal firing in SHR vs. WKY neurons. Chronic treatment with Ang (1–7) (100nM, 24 hrs) and inhibition of PI3K using lentiviral vector (LV‐DNp85α) significantly abolished Ang II mediated increase in neuronal firing rate in SHR vs. WKY neurons. Pretreatment of Ang (1–7) attenuated Ang II‐induced increase in the phosphorylation of Akt by 83% in SHR vs WKY neurons. Treatment with Ang (1–7) (100nM, 24 hrs) significantly enhanced PTEN expression in both WKY and SHR neuronal cultures using western blot and real‐time PCR. These effects of Ang (1–7) were blocked by A‐779 (10 μM), a Mas‐R antagonist. The data demonstrate that Ang (1–7) induces PTEN expression via Mas‐R, and depresses PI3K signaling via PKB/Akt pathway, which leads to a counter‐regulatory effect of Ang (1–7) on Ang II action in neuronal activity of SHR neurons.