TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension

Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-kappa B signaling pathway and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4 weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10 mu g/h), or losartan (LOS, 20 mu g/h), or the PPAR-gamma antagonist GW9662 (GW, 100 mu g/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-gamma, pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF kappa B) activity and plasma nor epinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-gamma in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-alpha, IL-1 beta, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-kappa B levels and increased PPAR-gamma level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-kappa B signaling and PPAR-gamma within the PVN are involved in the beneficial effects of telmisartan in hypertension. (C) 2016 Elsevier Inc All rights reserved.