Abstract
It is postulated that central effects 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 μM amastatin A or 100 μM 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. The 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 affect Ang II- or Ang III-induced astrocyte growth. These findings suggest that both peptides directly induce phosphorylation of these MAP kinases as well as induce astrocyte growth. These studies establish both peptides as biologically active with similar intracellular and physiological effects.
Highlights
Mitogen-activated protein (MAP) kinases constitute a superfamily of serine/threonine protein kinases involved in the regulation of a number of intracellular pathways associated with cellular growth, apoptosis, cellular differentiation, transformation of cells, and vascular contraction [1,2,3,4]
We have established that Ang II induces the phosphorylation of stressactivated protein kinase/Jun-terminal kinase (SAPK/JNK) MAP kinases leading to cellular proliferation in cultured rat astrocytes, an effect that was mediated by the AT1 Ang receptors [7]
We showed that Ang III induces the phosphorylation of ERK1/2 and SAPK/JNK MAP kinases in these cells [9, 10]
Summary
Mitogen-activated protein (MAP) kinases constitute a superfamily of serine/threonine protein kinases involved in the regulation of a number of intracellular pathways associated with cellular growth, apoptosis, cellular differentiation, transformation of cells, and vascular contraction [1,2,3,4]. We have shown that angiotensin (Ang) II via activation of AT1 receptors increases the expression of MAP kinases in primary cultures of rat astrocytes [5,6,7]. 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 established that Ang II induces the phosphorylation of stressactivated protein kinase/Jun-terminal kinase (SAPK/JNK) MAP kinases leading to cellular proliferation in cultured rat astrocytes, an effect that was mediated by the AT1 Ang receptors [7]. We showed that Ang III induces the phosphorylation of ERK1/2 and SAPK/JNK MAP kinases in these cells [9, 10]. Ang III induced astrocyte growth, not to a similar extent as Ang II [9]
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