Regulation of Angiotensinogen Expression by Angiotensin II in Spontaneously Hypertensive Rat Primary Astrocyte Cultures

BACKGROUND: Angiotensin (Ang) II, a bio-peptide of the renin-angiotensin system (RAS), plays a pivotal role in biological systems. It has been well established that in the brain, astrocytes are the predominant source for angiotensinogen (AGT), which is the precursor molecule for Ang II. The primary objective of this study was to determine the effect of Ang II on AGT mRNA and protein expression levels in primary cultures of astrocytes isolated from the brainstem and cerebellum regions of spontaneously hypertensive rats (SHRs) and normotensive Wistar rats.

METHODS: Astrocytes were treated with 100nM Ang II and the effect of time and the receptors involved in AGT mRNA and protein expression were measured using qPCR, and western blotting techniques, respectively.

RESULTS: Ang II significantly downregulated AGT mRNA levels and upregulated AGT protein levels in both SHR and Wistar rat astrocytes. Basal AGT mRNA levels in SHR samples were significantly lower as compared to Wistar astrocytes isolated from brainstem and cerebellum. There was no difference in the basal AGT protein levels when SHR and Wistar samples were compared. There was a tendency for higher Ang II-induced AGT protein levels in SHR samples compared to normotensive controls, but the difference was not significant. Ang II tended to decrease AGT mRNA levels of Wistar samples to a greater degree than SHR samples. The Ang AT1 receptor mediated the actions of Ang II on AGT protein and mRNA levels.

CONCLUSION: These findings highlight the complexity of AGT regulation and show that AGT protein and mRNA levels are responsive to Ang II in both SHR and Wistar astrocytes. Most importantly, our findings suggest that this peptide can induce its own synthesis by positively regulating AGT protein synthesis, an effect that was more robust in SHR astrocytes. Thus, dysregulation of this system may be important in preserving the hypertensive phenotype in this model.