Mechanistic insights into the therapeutic potential of Angiotensin type 2 receptors (AT2R) in shaping behavior of astrocytes and microglia during hypertensive state

Abstract

AbstractBackgroundAstrocytes are the major glial cell type in the central nervous system (CNS) and play a critical role in the pathogenesis of neuroinflammatory and neurodegenerative diseases. In particular, astrocytic activation during neuroinflammatory conditions perpetuates the inflammatory response and brain damage and neurodegeneration. Conversely, Angiotensin type 2 receptor (AT2R) activation is known to promote neuroprotection.MethodTherefore, the present study evaluated the role of AT2R in astrocytic activation in vitro in primary astrocytes and in vivo in hypertensive rats.ResultHere, we demonstrated that Ang II‐induced astrogliosis in primary astrocytes as apparent from increased expression of GFAP and iNOS, ROS generation, inflammatory imbalance and mitochondrial dysfunction in the primary astrocytes. On the contrary, AT2R activation by CGP42112A (CGP) abrogated Ang II induced astrocytic activation by inhibition of ROS production, mitochondrial dysfunction and inflammatory imbalance. However, this anti‐inflammatory action of AT2R activation by CGP was reversed by AT2R antagonist, PD123319 in both in vitro and in vivo conditions. Mechanistically, we found that AT2R via protein phosphatase‐2A (PP2A) activation abrogated the Ang II induced NFкB activation, ROS generation and consequent pro‐inflammatory activation of astrocytes. Importantly, PP2A antagonist, okadaic acid, reversed the anti‐inflammatory action of CGP to the comparable level as that by AT2R antagonist PD123319.ConclusionThus, the present study suggests that AT2R by the activation of PP2A abrogates the NFкB inflammatory signalling and inflammatory activation of astrocytes. Therefore, the therapeutic strategies targeting AT2R might be advantageous for neuroinflammatory or degenerative diseases perpetuated by astrocytic activation.