Abstract 226: Elevated Brain MCP-1 Contributes to Neuroinflammation in Hypertension
Inflammation has been identified as a major contributor to hypertension, and increased inflammation is associated with activation of the renin-angiotensin system (RAS). In this study we hypothesized that the activated RAS increases monocyte attractant protein (MCP)-1, which recruits immune cells (both resident microglia and circulating monocytes) to the paraventricular nucleus (PVN),contributing to the elevated sympathetic tone in hypertension. Treatment of primary neurons cultured from the hypothalamus of newborn SD rats with Ang II or prorenin significantly increased the levels of MCP-1 in the medium (Con: 58±7; Ang II: 191±18; prorenin: 213±23 ng/ml). To determine the effects of MCP-1 on the recruitment of resident microglia, we examined primary microglial migration using a cell migration kit. MCP-1 caused a dose-dependent (10-100 ng/ml) increase in microglial migration (Con: 0±2.9; MCP-1 at 10 ng/ml: 3.7±1.3; 50 ng/ml: 10.7±1.7; 100 ng/ml: 35.2±2.6; unit is arbitrary). In comparison to normotensive WKY rats, SHR exhibited significant increases in blood pressure (148±5 mmHg vs. 98±7 mmHg, n=5 each group). The levels of MCP-1 were dramatically increased in blood serum (77±3.6 vs. 30±0.5ng/ml), cerebrospinal fluid (18±0.9 vs. 3±0.3 ng/ml), and PVN tissues (35±0.5 vs. 4±0.4 ng/ml) of the SHR vs. WKY rats. Bone marrow-derived monocytes dissociated from the same animals were found to express high levels of CCR2 mRNA (4 fold greater in SHR vs. WKY rats), the primary receptor for MCP-1. To examine whether there was an effect of MCP-1 on monocyte recruitment, the ability of monocytes to elicit migration was compared in SHR and WKY rats. The results showed that the migration of WKY monocytes reached a plateau by 50 ng/ml MCP-1. In contrast, SHR monocytes were recruited by MCP-1 in a dose-dependent manner (10-100 ng/ml). At 100 ng/ml, MCP-1 was significantly more effective in recruiting monocytes from SHR than WKY (94±5 vs. 38±6; unit is arbitrary). In summary, these data suggest that RAS components can increase MCP-1 expression, which in turn recruits immune cells such as resident microglia and circulating monocytes. The present study suggests a potential mechanism by which inflammation contributes to hypertension in the presence of RAS activation.
- © 2012 by American Heart Association, Inc.