Blockade of angiotensin-converting enzyme or tumor necrosis factor-α reverses maternal high-fat diet-induced sensitization of angiotensin II hypertension in male rat offspring

Abstract

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

Keywords: blood pressure; inflammation; maternal high-fat diet; renin-angiotensin system.

Fig. 1.

Pressor effects (A and B) and heart rate (HR) (C) changes induced by ANG II in maternal normal fat diet (NFD) offspring and high-fat diet (HFD) offspring with pretreatment with captopril (Cap). The enhanced pressor effect in HFD offspring was attenuated by Cap pretreatment. (n = 6/group; two-way ANOVA, *P < 0.05 vs. baseline; #P < 0.05 vs. NFD offspring or HFD offspring with Cap pretreatment). MAP, mean arterial pressure.

Fig. 2.

Pressor effects (A and B) and heart rate (HR) (C) changes induced by ANG II in maternal normal fat diet (NFD) offspring and high-fat diet (HFD) offspring with pretreatment with pentoxifylline (PTX). The enhanced pressor effect in HFD offspring was attenuated by PTX pretreatment. (n = 6/group; two-way ANOVA, *P < 0.05 vs. baseline; #P < 0.05 vs. NFD offspring or HFD offspring with PTX pretreatment). MAP, mean arterial pressure.

Fig. 3.

Quantitative comparison of the mRNA expression of renin-angiotensin system components, proinflammatory cytokines, and NADPH oxidase in the lamina terminalis (LT) and paraventricular nucleus (PVN) in maternal normal fat diet (NFD) offspring and high-fat diet (HFD) offspring with pretreatment with captopril (Cap) before ANG II infusion (A and B). (n = 5/group; one-way ANOVA, *P < 0.05 vs. NFD offspring; #P < 0.05 vs. HFD offspring without pretreatment). AGT, angiotensinogen; ACE, angiotensin-converting enzyme; AT1-R, ANG II type 1 receptor; TNF-α, tumor necrosis factor-α; IL, interleukin; NOX2, NADPH oxidase.

Fig. 4.

Quantitative comparison of the mRNA expression of renin-angiotensin system components, proinflammatory cytokines and NADPH oxidase in the lamina terminalis (LT) and paraventricular nucleus (PVN) in maternal normal fat diet (NFD) offspring and high-fat diet (HFD) offspring with pretreatment with pentoxifylline (PTX) before ANG II infusion (A and B). (n = 5/group; one-way ANOVA, *P < 0.05 vs. NFD offspring; #P < 0.05 vs. HFD-offspring without pretreatment). AGT, angiotensinogen; ACE, angiotensin-converting enzyme; AT1-R, ANG II type 1 receptor; TNF-α, tumor necrosis factor-α; IL, interleukin; NOX2, NADPH oxidase.

Fig. 5.

Changes in body weight (A and B), food intake (C and D), and drinking water intake (E and F) during pretreatment with captopril (Cap) in maternal normal fat diet (NFD) offspring and high-fat diet (HFD) offspring after weaning. (n = 6/group; one-way ANOVA, *P < 0.05 vs. NFD offspring; #P < 0.05 vs. HFD offspring with Cap pretreatment).

Fig. 6.

Changes in body weight (A and B), food intake (C and D) and drinking water intake (E and F) during pretreatment with pentoxifylline (PTX) in maternal normal fat diet (NFD) offspring and high-fat diet (HFD) offspring after weaning. (n = 6/group; one-way ANOVA, *P < 0.05 vs. NFD offspring).