Hindawi Publishing Corporation International Journal of Hypertension Volume 2013, Article ID 782861, 8 pages http://dx.doi.org/10.1155/2013/782861 Research Article Distinct Molecular Effects of Angiotensin II and Angiotensin III in Rat Astrocytes Michelle A. Clark, Chinh Nguyen, and Hieu Tran Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA Correspondence should be addressed to Michelle A. Clark; miclark@nova.edu Received 29 November 2012; Revised 4 January 2013; Accepted 7 January 2013 Academic Editor: Marc de Gasparo Copyright © 2013 Michelle A. Clark et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It is postulated that central efects of angiotensin (Ang) II may be indirect due to rapid conversion to Ang III by aminopeptidase A (APA). Previously, we showed that Ang II and Ang III induced mitogen-activated protein (MAP) kinases ERK1/2 and stress- activated protein kinase/Jun-terminal kinases (SAPK/JNK) phosphorylation in cultured rat astrocytes. Most importantly, both peptides were equipotent in causing phosphorylation of these MAP kinases. In these studies, we used brainstem and cerebellum astrocytes to determine whether Ang II’s phosphorylation of these MAP kinases is due to the conversion of the peptide to Ang III. We pretreated astrocytes with 10 M amastatin A or 100 M glutamate phosphonate, selective APA inhibitors, prior to stimulating with either Ang II or Ang III. Both peptides were equipotent in stimulating ERK1/2 and SAPK/JNK phosphorylation. he APA inhibitors failed to prevent Ang II- and Ang III-mediated phosphorylation of the MAP kinases. Further, pretreatment of astrocytes with the APA inhibitors did not afect Ang II- or Ang III-induced astrocyte growth. hese indings suggest that both peptides directly induce phosphorylation of these MAP kinases as well as induce astrocyte growth. hese studies establish both peptides as biologically active with similar intracellular and physiological efects. 1. Introduction Mitogen-activated protein (MAP) kinases constitute a super- family of serine/threonine protein kinases involved in the regulation of a number of intracellular pathways associ- ated with cellular growth, apoptosis, cellular diferentiation, transformation of cells, and vascular contraction [1–4]. We have shown that angiotensin (Ang) II via activation of AT 1 receptors increases the expression of MAP kinases in primary cultures of rat astrocytes [5–7]. ERK1/2 MAP kinases were shown to mediate Ang II-induced astrocyte growth and Ang II-induced c-Fos and c-Myc expression [5, 6, 8]. We have also established that Ang II induces the phosphorylation of stress- activated protein kinase/Jun-terminal kinase (SAPK/JNK) MAP kinases leading to cellular proliferation in cultured rat astrocytes, an efect that was also mediated by the AT 1 Ang receptors [7]. Our indings suggest that Ang II signals through these two diferent MAP kinase pathways in astrocytes. More recently, we showed that Ang III also induces the phosphorylation of ERK1/2 and SAPK/JNK MAP kinases in these cells [9, 10]. Moreover, Ang III was equipotent to Ang II in causing these MAP kinases phosphorylation and occurred via interaction with the Ang AT 1 receptor. Ang III also induced astrocyte growth, however, not to a similar extent as Ang II [9]. Similar to our intracellular indings, in vivo studies have established that both peptides have similar physiologically relevant efects. For example, intracerebroventricular (ICV) injection of Ang II or Ang III caused a similar dose- dependent increase in blood pressure. Since Ang II is quickly cleaved by aminopeptidase A (APA) into Ang III, the true efector was unknown [11, 12]. In spontaneously hypertensive rats (SHR), injection of both peptides caused a prolonged blood pressure response compared to controls. However, pretreatment with bestatin, an aminopeptidase B (APB) inhibitor, potentiated and prolonged the elevated blood pressure response to Ang III in SHR [13]. Since bestatin