Abstract 163: Prorenin-induced Pro-inflammatory Effect In Hypothalamic Astrocytes From Spontaneously Hypertensive Rats

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Over-activation of the renin-angiotensin system (RAS) at the paraventricular nucleus of the hypothalamus (PVN) enhances the central immune response contributing to the development and maintenance of neurogenic hypertension. Astrocytes contribute to the production and secretion of pro-inflammatory cytokines (PICs) and are a vital component of the innate immune response in the brain. The contribution of astrocyte activation during hypertension has not been investigated and the actions of prorenin (PRO) on this cell type are undefined. Astrocytes cultured from the hypothalamus of normotensive rats (Sprague Dawley; SD) or spontaneously hypertensive rats (SHR; a model of neurogenic hypertension), contain (pro)renin receptor mRNA. When compared with non-treated cells (SD: 1.0 ± 0.04; SHR: 1.0 ± 0.05), treatment of SD cultures with PRO (60 nM; 3 h) increased the mRNA levels (normalized to GAPDH) of the PICs interleukin-6 (IL-6; 2.5 ± 0.3), interleukin-1β (IL-1β; 46.7 ± 12.1) and tumor necrosis factor-α (TNF-α; 13.8 ± 2.9) (n=6; p<0.05). In SHR cells, the PIC levels after PRO treatment were 5.0 ± 0.9 (IL-6), 133.6 ± 34.9 (IL-1β) and 59.9 ± 30.8 (TNF-α) (n=5). PIC production by PRO was significantly (p < 0.05) enhanced in SHR cultures. Treatment of astrocytes with angiotensin II (Ang II; 100 nM) or angiotensin III (Ang III; 100 nM & 1 μM) failed to increase PIC mRNA levels. PRO treatment also increased the levels of lipocalin-2 (LCN-2; p < 0.05), an early marker of astrogliosis, in astrocytes from both strains and this effect was enhanced in SHR cells (3.1 ± 0.6 vs. 6.7 ± 2.4). Evidence of astrogliosis (p < 0.05) was apparent in the PVN of adult SHR brain at different stages of hypertension development (9, 12 and 16 weeks of age; 10.6 ± 0.5, 9.9 ± 0.7 and 8.9 ± 0.7 [astroglial fractional area in PVN; AfaPVN], n=4 per age group), based on glial fibrillary acidic protein (GFAP) immunostaining and quantification using Image J. Age-matched SD or Wistar Kyoto rats exhibited lower GFAP-positive staining in the PVN (6.2 ± 0.6; 4.7 ± 1.3; 5.2 ± 1.2, AfaPVN, n=4 per age group). Our findings indicate that PRO, not Ang II or III, activates hypothalamic astrocytes inducing a pro-inflammatory response, possibly contributing to the astrogliosis observed in the PVN of adult SHR.

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