Modulating the renin-angiotensin system by eprosartan or xanthenone drives microglial M2 polarization in a rat model of Parkinson’s disease via regulating the interplay between MKP-1/ miR-155 /SOCS1 and PP2A signaling network

Abstract

Despite growing evidence for the renin-angiotensin system (RAS) involvement in Parkinson’s disease (PD), its role in microglial polarization during disease progression remains unclear. This study explored the ability of modulating RAS using eprosartan, an AT1R antagonist, and xanthenone, an ACE2 activator, to support microglial M2 polarization in rats with PD highlighting the roles of miR-155, protein phosphatase 2 A (PP2A), and mitogenactivated protein kinase phosphatase 1 (MKP-1). Rotenone (1.5 mg/kg) was administered to Wistar rats to induce PD, with concurrent treatments of eprosartan (60 mg/kg/day) or xanthenone (2 mg/kg/day) for 28 days. Both agents improved motor function and neuronal damage, as evidenced by behavioral, histopathological, and immunohistochemical analyses. Eprosartan and xanthenone enhanced tyrosine hydroxylase activity and reduced α-synuclein accumulation in the substantia nigra. Eprosartan and xanthenone modulated the RAS axis by reducing angiotensin II level and increasing ACE2 activity and Ang 1–7 concentration in the striatum. Importantly, these agents induced a shift in microglial polarization from the M1 proinflammatory phenotype (marked by reduced IL-1β, iNOS, and CD86) to the M2 anti-inflammatory phenotype (marked by enhanced arginase1, Ym1, Fizz1 and CD163). This shift was associated with altered STAT signaling pathways, including decreased pSTAT1 and increased p-STAT6. Additionally, levels of miR-155 were decreased, and levels of SOCS1, MKP-1, and PP2A were increased. These findings address a critical gap in understanding how RAS modulation can influence neuroinflammation through microglial polarization via regulating the interplay between MKP-1/ miR-155 /SOCS1 and PP2A, offering a promising therapeutic strategy to mitigate neurodegeneration and inflammation in PD.