Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension

Abstract

Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-α synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-α, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines.

Keywords: angiotensin II; blood pressure; high-fat diet; proinflammatory cytokine; sensitization.

Figure 1

Augmented pressor effects induced by Ang II during the expression (E) period in rats after pretreatment with HFD during the induction (I) period. This effect was attenuated by central inhibition of TNF-α synthesis, AT1-R or microglia activation (Fig. 1A). Figure 1B shows the changes in MAP after infusion of Ang II during E in all groups. Figure 1C shows the decreases in MAP in response to ganglionic blockade with hexamethonium at baseline, after 3 weeks of diet treatment and on day 14 after infusion of Ang II in all groups. I-NFD = pretreatment with normal fat diet during I; I-HFD = pretreatment with high fat diet during I; icv V = central treatment with vehicle during I; I-HFD+icv PTX = pretreatment with HFD plus central treatment with TNF-α synthesis inhibitor pentoxifylline during I; I-HFD+icv Irbe = pretreatment with HFD plus central treatment with AT1-R blocker irbesartan during I; I-HFD+icv Mino = pretreatment with HFD plus central treatment with inhibitor of microglial activation minocycline during I; E-saline = peripheral treatment with saline during E; E-Ang II = peripheral treatment with a pressor dose of Ang II during E. (* significant difference vs. baseline or after diet treatment; # significant difference vs. I-NFD+icv V + E-Ang II and other groups fed with HFD plus central blocker treatment during I)

Figure 2

Changes in caloric intake (A), feed efficiency (B) and body weight (C) in normal fat diet (NFD) rats and high fat diet (HFD) rats treated with central (icv) TNF-α, synthesis inhibitor pentoxifylline (PTX), AT1-R blocker irbesartan (Irbe) or inhibitor of microglial activation minocycline (Mino) before and after systemic infusion of a pressor dose of Ang II. (* significant difference vs. before Ang II; # significant difference vs. NFD rats; § significant difference vs. HFD groups).

Figure 3

Quantitative comparison of the mRNA expression of renin-angiotensin system components (A), proinflammatory cytokines and microglial marker (B) in the lamina terminalis (LT) of rats fed normal fat diet (NFD) or high fat diet (HFD) and treated with central (icv) infusion of TNF-α synthesis inhibitor pentoxifylline (PTX), AT1-R blocker irbesartan (Irbe) or inhibitor of microglial activation minocycline (Mino) during induction (I). (* significant difference vs. NFD; # significant difference vs. HFD with icv vehicle).

Figure 4

Augmented pressor effects induced by Ang II during the expression (E) period in rats after central treatment with TNF-α or subpressor dose of Ang II during the induction (I) period (Fig. 4A). The sensitizing effect of subpressor dose of Ang II was attenuated by central inhibition of either TNF-α synthesis or microglia activation. Figure 4B shows the changes in MAP after infusion of Ang II during E in all groups. icv V = central treatment with vehicle during I; icv TNF-α = central treatment with TNF-α during I; icv Ang II = central treatment with subpressor dose of Ang II during I; I-icv Ang II/PTX = central concurrent treatment with subpressor dose of Ang II and TNF-α synthesis inhibitor pentoxifylline during I; I-icv Ang II/Mino = central concurrent treatment with subpressor dose of Ang II and inhibitor of microglial activation minocycline during I; E-Ang II = peripheral treatment with a pressor dose of Ang II during E. (* significant difference vs. baseline; # significant difference vs. I-icv V + E-Ang II and other groups treated with central blocker during I).

Figure 5

Quantitative comparison of the mRNA expression of renin-angiotensin system components (A), proinflammatory cytokines and microglial marker (B) in the lamina terminalis (LT) of rats receiving central (icv) infusion of TNF-α, subpressor dose of Ang II or subpressor dose of Ang II plus TNF-α synthesis inhibitor pentoxifylline (PTX) or inhibitor of microglial activation minocycline (Mino) during induction (I). (* significant difference vs. icv vehicle; # significant difference vs. icv Ang II)