Abstract
Angiotensin II receptor type 2 (AT2R) agonists have been known to promote neuroprotection by limiting ischemic insult, neuronal proliferation, and differentiation. Further, AT2R agonists have also been associated with the suppression of neuroinflammation and neurodegeneration. Of note, brain astrocytes play a critical role in these neuroinflammatory and neurodegenerative processes. However, the role of AT2R in astrocytic activation remains elusive. Therefore, this study evaluated the role and molecular mechanism of AT2R agonist CGP42112A (CGP) against Angiotensin II (Ang II)-induced astrocytic activation in primary astrocytes, and in a rat model of hypertension. Here, we demonstrated that AT2R activation by CGP abrogated Ang II-induced astrocytic activation, by mitigating the ROS production, mitochondrial dysfunction, IκB-α degradation, NFκB nuclear translocation, and release of TNF-α in astrocytes. However, AT2R-mediated anti-inflammatory effects were reversed by AT2R antagonist, PD123319 (PD), in both in vitro and in vivo conditions. Mechanistically, AT2R via protein phosphatase-2A (PP2A) abrogated the Ang II-induced NFκB activation, ROS generation, and subsequent astrocytic activation. Importantly, PP2A antagonist, okadaic acid, reversed the anti-inflammatory effects of AT2R in Ang II-stimulated primary astrocytes and in the cortex of hypertensive rats. Thus, the present study suggests that AT2R by activating PP2A inhibits oxidative stress and NFκB activation, thereby preventing the astrocytic pro-inflammatory activation. Therefore, AT2R might be advantageous therapeutic target for neuroinflammatory/neurodegenerative diseases perpetuated by astrocytic activation.
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Acknowledgements
We are highly thankful to Mr. A. L. Vishwakarma, Mrs. M. Chaturvedi, and Mr. Dhananjay Sharma for their help with the flow cytometry and confocal microscopy procedures. We also acknowledge THUNDER (BSC0102) and MoES (GAP0118) for the confocal facility. The CSIR-CDRI communication number of this article is 10278.
Funding
The study was supported by a financial grant to Kashif Hanif from Department of Biotechnology (DBT, Grant No. BT/PR4021/MED/30/676/2011) and CSIR Network Project MIND (BSC0115). Award of research fellowships to SAB from the Indian Council of Medical Research (ICMR), New Delhi and AS from NIPER, Rae Bareli, are greatly acknowledged.
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S.A.B. designed study, performed experiments, analyzed data, prepared the figures, and wrote the manuscript. Z.F. and A.S. performed in vitro experiments and data analysis. R.S. did critical reading and editing of the manuscript and provided the chemicals. K.H. conceptualized, planned, supervised the study, and edited the manuscript. All the authors have read and approved the final manuscript.
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Bhat, S.A., Fatima, Z., Sood, A. et al. The Protective Effects of AT2R Agonist, CGP42112A, Against Angiotensin II-Induced Oxidative Stress and Inflammatory Response in Astrocytes: Role of AT2R/PP2A/NFκB/ROS Signaling. Neurotox Res 39, 1991–2006 (2021). https://doi.org/10.1007/s12640-021-00403-4
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DOI: https://doi.org/10.1007/s12640-021-00403-4