ABSTRACT
Background
Physical activity has profound benefits on health, especially in patients with cardiovascular and metabolic disease. Exercise training can reduce oxidative stress, improve renal function, and thus lower blood pressure. However, the effect of exercise training on angiotensin II type 1 receptors (AT1R) and endothelin subtype B receptors (ETBR)-mediated diuresis and natriuresis in obese Zucker rats is unclear.
Methods
Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. Blood pressure was measured by tail-cuff plethysmography, and functions of AT1R and ETBR in the kidney were measured by natriuresis, respectively.
Results
Our data showed that exercise training improved glucose and lipid metabolism, renal function and sodium excretion in obese Zucker rats, accompanied by decreased oxidative stress and GRK4 expression in obese Zucker rats. Moreover, exercise training reduced the Candesartan-induced an increase in diuresis and natriuresis and increased ETBR agonists (BQ3020)-mediated diuresis and natriuresis in obese Zucker rats, which were associated with decreased renal AT1R expression and ETBR phosphorylation levels.
Conclusions
The results demonstrate that exercise training lowers blood pressure via improving renal AT1R and ETBR function through modulating GRK4 expression in Obese Zucker Rats and provides potentially effective targets for obesity-related hypertension.
Cardiovascular disease (CVD) remains the leading causes of disability and death worldwide due to the majority of patients co-existing with obesity and diabetes.Citation1 Numerous epidemiological studies have shown that chronic exercise has a significant protective benefit in patients with hypertension, diabetes, or obesity.Citation2 Therefore, chronic exercise has been recommended as a non-pharmacological treatment for metabolic related diseases such as hypertension, diabetes and obesity.
Hypertension, diabetes and obesity are characterized by a tendency to retain sodium.Citation3 Especially in obese and diabetic patients, increased sodium retention can cause further increases in blood pressure, which is ascribed, at least in part, to an imbalance between antinatriuretic factors and natriuretic factors.Citation4 As an important part of the antidiuretic system, the renal renin-angiotensin-aldosterone system (RAAS) plays a role in inhibiting sodium excretion by acting on angiotensin II type 1 receptor (AT1R).Citation5 The expression of AT1R was significantly increased in many animal models of hypertension and in patients with hypertension.Citation6,Citation7 Inhibition of AT1R expression and function can significantly reduce blood pressure and improve long-term prognosis of hypertensive patients.Citation8 As an important diuretic factor, endothelin subtype B (ETB) receptor plays an important role in sodium excretion of kidney, which has received extensive attention in recent yearsCitation9. Therefore, the regulation of renal AT1R or ETB receptor (ETBR) expression and function is one of the important strategies for the treatment of hypertension.
Previous studies have shown that the relevant receptors in kidney responsible for sodium excretion, including angiotensin, dopamine and ETB receptor, belong to the family of G protein-coupled receptors.Citation10 The function of these receptors is regulated by G protein-coupled receptor kinases, of which GRK4 is one of the most common subtypes that promote G protein-coupled receptor phosphorylation.Citation11 Previous studies have shown that exercise is one of the important non-drug treatment strategies for improving obesity-related complications.Citation12 However, whether exercise can improve renal AT1R and ETBR function in obesity-related hypertension, and whether GRK4 plays a corresponding role in this process, which is unknown. The purpose of the current study was to evaluate whether exercise training improves renal AT1R and ETBR function via modulating GRK4, thereby reducing obesity-related hypertension.
Materials and methods
Animal
Male obese and lean Zucker rats (10 weeks) were purchased from Vital River Laboratory Animal Technology in Beijing, China, and housed in plastic cages with free access to standard rodent chow and drinking water. This study was conformed to the National Institutes of Health guidelines, and the protocols were approved by the Committee on Animal Care of Guangzhou University of Chinese Medicine.
Experimental protocol
Obese and lean rats were randomly divided into sedentary and exercise groups. To allow for animal acclimatization, exercise duration and intensity were gradually increased over the first week of exercise exposure. Rats were exercised, 6 days/week, for 8 weeks, and sedentary groups were placed on a nonmoving treadmill for 8 weeks. Blood pressure and heart rate for all animals were measured at baseline (10 week-old of age) and then every week until the end of the study by a CODA noninvasive tail-cuff system (BP-98A; Softron, Tokyo, Japan). At the end of the study, the rats were placed in metabolic cages for 24 h urine collection. The levels of total cholesterol (TC), triglycerides (TG), creatinine (Cr) and blood urea nitrogen (BUN) were measured using biochemical analyzer (Polymer Technology Systems, Cardiochek, IN). Fasting glucose was measured with a glucose analyzer (Accuchek, Roche Diabetes Care, Paris, France), and plasma insulin was measured by radioimmunoassay using a rat insulin kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China). For intraperitoneal glucose tolerance test (GTT), mice were fasted for 6 h and received an intraperitoneal injection of glucose (1 g/kg body weight).
Surgical procedures for renal function studies
Surgical procedures for renal function studies were performed as described previously.Citation13 Rats were anesthetized with pentobarbital (50 mg/kg body wt, intraperitoneally, Sigma, MO, USA) and prepared for the measurement of blood pressure and intravenous drug administration. The effect of AT1R antagonist Candesartan or ETB receptor agonist BQ3020 on sodium excretion was determined in all four groups. The protocol consisted of a 45-min stabilization period after the surgery followed by three consecutive 40-min collection periods: basal period, experimental and recovery period. During basal period, saline alone was infused; during experimental period, candesartan (10 μg/kg/min) or BQ3020 (1 μg/kg/min) was infused; and during recovery period, only saline was infused. Urine flow and urinary sodium excretion (UNaV) were recorded for each period.
Indexesof oxidative stress
The kidneys were quickly removed, and the renal cortices were extracted by methanol. Renal malondialdehyde (MDA) and glutathione (GSH) concentrations were measured by assay kit (Beyotime, Shanghai, China). 8-isoprostane in urine was measured by RIA kit (516351; Cayman, Ann Arbor, MI).
Western blot analysis
Protein samples from renal cortices homogenates underwent SDS-PAGE and were transferred to nitrocellulose membranes. The membranes were probed with primary antibodies against GRK4 (1:300 dilution; Abcam, Cambridge, UK), AT1R (1:300 dilution; Abcam, Cambridge, UK), ETBR (1:500 dilution; Abcam, Cambridge, UK) and GAPDH (1:800 dilution; Abcam, Cambridge, UK) at 4°C overnight followed by incubation with horseradish peroxidase-conjugated secondary antibodies (DakoCytomation, Carpinteria, CA). The bound complex was detected using the Odyssey Infrared Imaging System, and the images were analyzed using Quantity One software.
Immunoprecipitation
Immunoprecipitation was performed as described previously (Citation13). In brief, the renal cortex was lysed and incubated with affinity-purified anti-phosphoserine or ETBR antibody (Abcam) for 1 h and protein G plus-agarose overnight at 4°C. The immunoprecipitates were subjected to immunoblotting with rabbit anti-ETBR antibody (1:1000; Abcam) or anti-phosphoserine antibody. The bound complex was detected using the Odyssey Infrared Imaging System, and the images were analyzed using Quantity One software.
Statistical analysis
The data were expressed as mean±SD. Statistical analysis was carried out using the GraphPad Prism 5.0 software. Data were analyzed using one-way or two-way ANOVA followed by Newman–Keuls post hoc test whenever appropriate. The value of p < .05 was considered significant.
Results
Exercise training improved glucose and lipid metabolism and decreased blood pressure in obese Zucker rats
Consistent with previous studies (Citation14), obese rats with exercise training showed significant lower weight (). Regarding the effect of exercise training on insulin resistance, we observed that obese rats exhibited higher fasting glucose levels, fasting insulin levels and impaired glucose tolerance, determined by IPGTT, which were markedly reversed by exercise training (). Moreover, exercise training decreased the levels of TG, TC, blood pressure and heart rates in obese rats (). However, exercise training had no effect on the above related metabolic indexes in lean rats.
Figure 1. The effects of exercise training on glucose and lipid metabolism and blood pressure in obese Zucker rats. Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. (a) Body weight. (b and c) fasting blood glucose and serum insulin levels. (d) IPGTT (intraperitoneal glucose tolerance test). (e) Serum TG levels. (f) Serum TC levels. (g) Systolic blood pressure (SBP) was measured from 10 to 18 weeks of age by tail-cuff plethysmography. (h) Heart rate levels in 18 weeks of age. Data were expressed as the means ± SD (n = 6/group). *p <.05 vs others. LZ+Sed, lean Zucker+Sedentary; LZ+Ex, lean Zucker+Exercise; OZ+Sed, obese Zucker+Sedentary; OZ+Ex, obese Zucker+Exercise.
Exercise training improved renal function and sodium excretion in obese Zucker rats
Consistent with previous studies (Citation15), obese rats showed some degree of renal insufficiency, mainly manifested by increased creatinine (Cr) and blood urea nitrogen (BUN) (). Moreover, obese rats had increased urinary volume output and sodium excretion, but after adjusting for body weight, urinary volume output and sodium excretion were indeed lower in obese than lean rats (). The renal dysfunction and impaired sodium excretion were reversed in obese rats with exercise training (). However, exercise training had no effect on the renal function and sodium excretion in lean rats.
Figure 2. Effect of exercise training on renal function and sodium excretion in obese Zucker rats. Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. (a and b) creatinine (cr) and blood urea nitrogen (BUN) levels. (c and d) 24 h urine volume and urinary sodium excretion (UNaV) were determined by metabolic cages. Data were expressed as the means ± SD (n = 6/group). *p <.05 vs others. LZ+Sed, lean Zucker+Sedentary; LZ+Ex, lean Zucker+Exercise; OZ+Sed, obese Zucker+Sedentary; OZ+Ex, obese Zucker+Exercise.
Exercise training reduced the expression and function of AT1R in obese Zucker rats
Previous studies have showed that, compared to lean rats, the expression and function of AT1R in obese Zucker rats were significantly enhanced (Citation7). To determine the effect of exercise training on renal AT1R function in obese and lean rats, AT1R antagonist Candesartan was perfused through the jugular vein to observe diuretic and natriuretic effects. These results showed that there were significantly greater increase in urine flow and UNaV in response to the AT1R antagonist Candesartan in obese Zucker rats (). Although exercise training had no effect in lean rats, the exaggerated diuretic and natriuretic responses to Candesartan were reduced with exercise training in obese Zucker rats (). More importantly, the expression of AT1R in the kidneys of obese rats was also significantly increased, which was reversed after exercise training ().
Figure 3. Effect of exercise training on the expression and function of AT1R in obese Zucker rats. Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. Urine flow (a) and urinary sodium excretion (UNaV) (b) were recorded during the vehicle or candesartan (10 μg/kg/minute) infusion via the jugular vein of rats. *p < .05 vs lean rats within the same treatment and #p < .05 vs obese rats within the same treatment using one-way ANOVA followed by Newman-keuls post hoc test. (c) AT1R protein expressions were determined by immunoblotting. Data were expressed as the means ± SD (n = 6/group). *p <.05 vs others. LZ+Sed, lean Zucker+Sedentary; LZ+Ex, lean Zucker+Exercise; OZ+Sed, obese Zucker+Sedentary; OZ+Ex, obese Zucker+Exercise.
Exercise training improved diuretic and natriuretic effects of ETBR in obese Zucker rats
Previous study found that stimulation of ETBR inhibited Na+-K+ ATPase activity in RPT cells from WKY rats (Citation13). The present study further showed that the infusion of the ETBR agonist BQ3020, via the jugular vein, induced diuresis and natriuresis in lean rats, but not in obese Zucker rats, indicating ETBR-mediated diuresis and natriuresis are impaired in obese Zucker rats (). ETBR, as a G protein-coupled receptor, is regulated by phosphorylation. Our present study showed that although there was no difference in ETBR expression in homogenates from renal cortices of lean and obese Zucker rats, renal cortical ETBR phosphorylation was greater in obese than lean rats (). Exercise training improved the impaired diuretic and natriuretic effects of ETBR and reduced the ETBR phosphorylation in obese Zucker rats ().
Figure 4. Effect of exercise training on ETBR-mediated diuresis and natriuresis in obese Zucker rats. Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. Urine flow (a) and urinary sodium excretion (UNaV) (b) were recorded during the vehicle or BQ3020 (1 μg/kg/min) infusion via the jugular vein of rats. *p < .05 vs lean rats within the same treatment and *p < .05 vs obese rats within the same treatment using one-way ANOVA followed by Newman-keuls post hoc test. (c) Renal cortical ETBR phosphorylation determined by coimmunoprecipitation with immunoblotting. Data were expressed as the means ± SD (n = 6/group). *p <.05 vs others. LZ+Sed, lean Zucker+Sedentary; LZ+Ex, lean Zucker+Exercise; OZ+Sed, obese Zucker+Sedentary; OZ+Ex, obese Zucker+Exercise.
Exercise training reduced GRK4 expression and oxidative stress in kidney of obese Zucker rats
The phosphorylation of GPCRs is regulated by GRKs, specifically GRK4. Our present study found that the protein expression of GRK4 was higher in the renal cortex of obese rats than that in lean rats, which was reversed by exercise training (). Previous studies have shown that the expression of GRK4 is regulated by oxidative stress. We checked the levels of oxidative stress in the renal cortex of rats and found that the renal cortical MDA and urinary 8-isoprostane level were higher, and the renal cortical GSH level was lower in obese than lean Zucker rats, which were reversed by exercise training ().
Figure 5. Effect of exercise training on GRK4 expression and oxidative stress in kidney of obese Zucker rats. Lean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. (a) GRK4 protein expressions were determined by immunoblotting. (b-d)The indices of oxidative stress included renal cortical MDA and urinary 8-isoprostane and renal cortical GSH level. Data were expressed as the means ± SD (n = 6/group). *p <.05 vs others. LZ+Sed, lean Zucker+Sedentary; LZ+Ex, lean Zucker+Exercise; OZ+Sed, obese Zucker+Sedentary; OZ+Ex, obese Zucker+Exercise.
Discussion
The results of our study showed that GRK4 played an essential role in exercise-induced improvement of AT1R and ETBR function in obese Zucker rats. Exercise ameliorated oxidative stress and inhibited an increase in GRK4 expression in obese Zucker rats accompanied by a decrease of AT1R expression and ETBR phosphorylation, which contributed to the reduction of blood pressure. Collectively, the data suggested that GRK4 acted as the major regulator in response to exercise to restore AT1R and ETBR function in obese Zucker rats.
There is emerging evidence that exercise helps to prevent cardiovascular disease in patients with diabetes and obesity through limiting oxidative stress (Citation16,Citation17). Studies on animal models of hypertension have shown that an increase in oxidative stress is accompanied by decreased renal D1 receptor signaling and increased renal AT1R function and that treatment of these animals with antioxidants normalizes BP and restores D1 and AT1 receptor function (Citation18,Citation19). Moreover, exercise ameliorates D1 receptor dysfunction and improves insulin sensitivity via regulation of GRK4 pathway (Citation20). Exercise alleviates endothelial mitochondrial fragmentation, which may contribute to improvement of vascular function and blood pressure in hypertension (Citation21). Consistent with other studies (Citation22), our study also found that exercise significantly reduced oxidative stress and blood pressure in obese Zucker rats. Therefore, exercise has been recommended as a nonpharmaceutical therapy to lower blood pressure in patients with hypertension via reducing oxidative stress.
AT1R is an important component of RAS, and its expression and function are significantly enhanced in the state of hypertension (Citation23). AT1R is widely expressed in the regulating organs of blood pressure and can act on the target organs of blood pressure regulation to play an important role in blood pressure regulation. In the kidney, activation of AT1R can mediate sodium retention (Citation24); in blood vessels, activation of AT1R can play a vasoconstrictive role (Citation25); in the paraventricular nucleus of the hypothalamus, activation of AT1R promotes neuronal excitation and activates peripheral sympathetic nerve activity (Citation26). Similar to the results of other studies (Citation27), our study also found that the expression and function of renal AT1R were significantly enhanced in obese Zucker rats. More importantly, we also found that exercise could reduce the expression and function of renal AT1R, which may be one of the important reasons for the reduction of blood pressure. With regard to exaggerated renal AT1R function in obese Zucker rats, it is likely that GRK4 increased the transcription and function of renal AT1R. This notion is based on previous studies demonstrating that NF-κB is a redox-sensitive transcription factor and AT1R gene promoter is reported to have a binding motif for NF-κB (Citation28). In addition, previous studies have shown that GRK4 regulates arterial AT1R expression and function via NF-κB pathway, which participates in the pathogenesis of hypertension (Citation29). Studies have shown that exercise can reduce oxidative stress, inhibit the transcription factor c-myc into the nucleus, and then reduce the binding of c-myc and GRK4 promoter, which is an important reason for reducing GRK4 expression (Citation20).
In addition to RAS, the endothelin system is also an important part of blood pressure regulation (Citation30). As aforementioned, ETBR belongs to the family of GPCRs. In hypertensive state, ETBR-mediated sodium excretion is significantly impaired (Citation31), and GRK4 regulates ETBR phosphorylation (Citation13), which is an important reason for impaired ETBR function. Our present study found that ETBR phosphorylation was higher in kidneys from obese Zucker than lean rats, which may explain the dysfunction of renal ETBR in obese Zucker rats. However, the exact phosphorylation site of ETBR still needs to be investigated. Previous study has found that renal D1R, D3R and ETBR functions are impaired in hypertension, which is related to their persistent hyper-phosphorylation caused by increased expression of GRK4 (Citation13,Citation32,Citation33). In our present study, we found that the expression of GRK4 was increased in obese Zucker rats and exercise downregulated GRK4 expression which decreased the basal renal ETBR phosphorylation and restored ETBR-mediated diuresis and natriuresis in obese Zucker rats.
A variety of different factors probably contribute to the enhanced AT1R function and the defect in ETBR function in obese Zucker rats. Obese Zucker rats exhibit hyperinsulinemia, hyperglycemia, dyslipidemia, and increased oxidative stress (Citation34), and, thus, all of these factors can contribute to the enhanced AT1R function and the impairment in ETBR function. Interestingly, in obese animals, antioxidant supplementation with tempol or exercise training improves insulin sensitivity, decreases plasma insulin and blood triglycerides, and normalizes blood glucose (Citation35,Citation36). Based on our observations, we suggested that the effect of exercise training was due to its ability to improve insulin sensitivity leading to normalization of blood glucose and a marked decrease in triglycerides. The decrease in circulating insulin, glucose, and triglycerides can further decrease oxidative stress and thus have a cumulative effect in reducing GRK4 expression and restoring the AT1R and ETBR function in obese Zucker rats.
In conclusion, the current study provided new insights into the benefits of physical exercise on lowering blood pressure via reducing oxidative stress and GRK4 expression, and improving AT1R and ETBR function. The current novel findings should help to arouse public awareness about the importance of physical activity to prevent the onset of obesity-related hypertension.
Author contribution
LJ conceived and designed the experiments and wrote the manuscript; LZ performed the experiments and analyzed the data; YY contributed reagents analysis tools; WF approved the final version of the manuscript
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request
Additional information
Funding
References
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