Activation of Central PPAR-γ Attenuates Angiotensin II–Induced Hypertension

Abstract

Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension.

Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor- Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5

“…Several studies showed that the rostral ventrolateral medulla contains high concentrations of AT 1 receptors (Head, 1996) and is a major site of the sympathoexcitatory action of central AngII. AT 1 receptor expression was upregulated by AngII in this area and in the subfornical organ, the paraventricular hypothalamic nuclei, and the solitary tract nuclei (Yoshimura et al, 2000;Yu et al, 2015). Thus, elevated central AngII may act to upreglulate AT 1 receptors in the brainstem.…”

Ultrastructural characterization of tumor necrosis factor alpha receptor type 1 distribution in the hypothalamic paraventricular nucleus of the mouse

“…Like glutamate, TNFα activity in the PVN is implicated in blood pressure control. Increased TNFα levels in the PVN, originating from a microglial source (Shi et al, 2010), are associated with the increased local neural activity (Kang et al, 2008, Yu et al, 2015), as well as elevated systemic blood pressure (Sriramula et al, 2013, Dai et al, 2015, Dange et al, 2015) and sympathetic activity (Dange et al, 2015, Yu et al, 2015) that accompany experimental hypertension (Shi et al, 2010, Yu et al, 2015). In addition, acute PVN TNFα administration increases sympathetic activity and blood pressure (Bardgett et al, 2014, Shi et al, 2014), and inhibiting central TNFα has been shown to block forms of experimental hypertension (Song et al, 2014) including the increase in blood pressure occurring with AngII administration (Sriramula et al, 2013).…”

“…Within the PVN, TNFα transcription is induced by challenges such as immunological stress (Kakizaki et al, 1999, Masson et al, 2015a). In addition, increased TNFα levels in the PVN are associated with increased local neural activity (Kang et al, 2008, Yu et al, 2015), as well as elevated systemic blood pressure (Sriramula et al, 2013, Dai et al, 2015, Dange et al, 2015) and sympathetic activity (Dange et al, 2015, Yu et al, 2015). All of these physiological responses accompany preclinical models of hypertension including the elevated blood pressure induced by angiotensin II (AngII), a critical blood pressure regulating molecule (Shi et al, 2010, Yu et al, 2015).…”

“…In addition, increased TNFα levels in the PVN are associated with increased local neural activity (Kang et al, 2008, Yu et al, 2015), as well as elevated systemic blood pressure (Sriramula et al, 2013, Dai et al, 2015, Dange et al, 2015) and sympathetic activity (Dange et al, 2015, Yu et al, 2015). All of these physiological responses accompany preclinical models of hypertension including the elevated blood pressure induced by angiotensin II (AngII), a critical blood pressure regulating molecule (Shi et al, 2010, Yu et al, 2015). Elevated PVN TNFα is also seen in spontaneously hypertensive rats (Masson et al, 2015b), as well as following models of heart failure (Guggilam et al, 2007, Wei et al, 2016) and acute myocardial infarction (Du et al, 2015).…”

Yixinshu ameliorates hippocampus abnormality induced by heart failureviathe PPARγ signaling pathway

“…34 On the other hand, the activation of brain PPARg in heart failure rats can reduce central inammation and brain renin-angiotensin system activity, ameliorating angiotensin II-induced hypertension in heart failure. 29,35 Thus, central PPARg may be the therapeutic target in treating hippocampus damage in myocardial infarction-induced HF. In present study, we found that PPARg was reduced in the hippocampus in rats with heart failure.…”