Chronic exercise modulates RAS components and improves balance between pro- and anti-inflammatory cytokines in the brain of SHR

Abstract

Recently, exercise has been recommended as a part of lifestyle modification for all hypertensive patients; however, the precise mechanisms of its effects on hypertension are largely unknown. Therefore, this study aimed to investigate the mechanisms within the brain that can influence exercise-induced effects in an animal model of human essential hypertension. Young normotensive WKY and SHR rats were given moderate-intensity exercise for 16 weeks. Blood pressure was measured bi-weekly by tail-cuff method. Animals were then euthanized; paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM), important cardiovascular regulatory centers in the brain, were collected and analyzed by Real-time RT-PCR, western blot, EIA, and fluorescent microscopy. Exercise of 16 weeks duration attenuated systolic, diastolic, and mean arterial pressure in SHR. Sedentary SHR exhibited increased proinflammatory cytokines (PICs) and decreased anti-inflammatory IL-10 levels in the PVN and RVLM. Furthermore, SHRsed rats exhibited elevated levels of ACE, AT1R, and decreased levels of ACE2 and receptor Mas in the PVN and RVLM. Chronic exercise not only prevented the increase in PICs (TNF-α, IL-1β), ACE, and AT1R protein expression in the brain of SHR, but also dramatically upregulated IL-10, ACE2, and Mas receptor expression in SHR. In addition, these changes were associated with reduced plasma AngII levels, reduced neuronal activity, reduced NADPH-oxidase subunit gp91phox and inducible NO synthase (iNOS) in trained SHRs indicating reduced oxidative stress. These results suggest that chronic exercise not only attenuates PICs and the vasoconstrictor axis of the RAS but also improves the anti-inflammatory defense mechanisms and vasoprotective axis of the RAS in the brain, which, at least in part, explains the blood pressure-lowering effects of exercise in hypertension.

High intensity interval training favourably affects antioxidant and inflammation mRNA expression in early-stage chronic kidney disease

“…This is noteworthy as decreased TNFRSF1B protein expression has been linked to increases in TNFα-induced apoptosis in cells that are crucial to immuno-regulation and inflammatory responses such as lymphocytes [32]. Considering our findings, in conjunction with findings that describe (a) the ability of chronic aerobic exercise to significantly reduce TNFα mRNA expression [33], (b) the inverse relationship between serum levels of TNFα and TNF receptors [34], and (c) the inverse relationship between TNFα-induced apoptosis and TNFRSF1B protein expression [32], we propose that HIIT favourably influences TNFα activity, as evidenced by an increase in the expression of Tnfrsf1b mRNA. Furthermore, based on our data, we propose the ability of exercise to influence TNFα activity is intensity-dependant as HIIT resulted in a significant up-regulation of Tnfrsf1b mRNA expression, compared to LIT (p=0.047).…”

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

“…PVN was isolated from frozen brain sections using a Stoelting brain punch (Stoelting) and, then, the tissue was homogenized with RIPA lysis buffer, as previously described (2,7,18,39). The protein concentration was measured using a bicinchoninic acid (BCA) protein assay kit (Pierce).…”

“…Immunofluorescence staining in the PVN was performed as previously reported (2,13,31). Briefly, sequential hypothalamic coronal sections (30 m, Ϫ1.80 to Ϫ2.12 caudal to the bregma, 3 rats/subgroup) were cut with a cryostat (Leica CM 1850; Nussloch, Germany) and collected in tissue culture wells with 0.1 M PB.…”

“…This major pathological feature in hypertension is closely related to endorgan injuries, as retinopathy, glomerular sclerosis, stroke, and myocardial infarction (25,42). Experimental studies from our group have shown that hypertensive rats had increased proinflammatory cytokines expression in autonomic control areas, such as the hypothalamic paraventricular nucleus (PVN) (2,31). In addition, it was demonstrated that acute microinjection of proinflammatory molecules into the PVN of normotensive rats causes elevation of both arterial pressure and renal sympathetic nerve activity (38).…”

“…Decreased tissue oxidative stress and inflammation were described as key mechanisms that contribute to these physiological benefits (31). In the PVN, we previously showed that ExT decreases the expression of proinflammatory cytokines and reduces the production of superoxide in spontaneously hypertensive rats (SHR), which attenuates hypertension and improves autonomic function (2,31). Improvement of cardiac vagal activity and baroreflex sensitivity was recently demonstrated after short-term ExT in experimental (31) and clinical (21) studies.…”