ABSTRACT
Background
Oxidative stress has been shown to play a critical role in the pathogenesis of hypertension. Paeonol, a major phenolic component extracted from Moutan Cortex, exerts a beneficial effect in preventing cardiovascular disease via reducing oxidative stress. The present study investigated the protective mechanism of paeonol against high blood pressure in spontaneous hypertension rats (SHRs).
Methods
Wistar-Kyoto (WKY) rats and SHRs received vehicle or peaonol in the drinking water for 5 weeks. Blood pressure was measured by tail-cuff plethysmography and oxidative stress in kidney and vascular tissue was examined by enzyme-linked immunosorbed assay. The functions of angiotensin II type 1 receptors (AT1R) in the kidney and mesenteric artery were measured by natriuresis and vasoconstrictor response, respectively.
Results
Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure, increased oxidative stress, accompanied by exaggerated diuretic and natriuretic responses to candesartan (AT1 receptor antagonist) and vasoconstrictor responses to angiotensin II (Ang II). Moreover, SHRs had higher ACE and AT1R in the kidney and mesenteric artery, and higher Ang II and lower renin levels. Interestingly, paeonol treatment reduced the candesartan-induced increase in diuresis and natriuresis and vasoconstrictor responses to Ang II, and lowered blood pressure in SHRs, accompanied by reducing AT1R protein expression in the kidney and mesenteric artery of SHR, and Ang II levels in plasma and increasing renin levels in renal cortex. In addition, these changes were associated with reducing oxidative stress.
Conclusions
The present study suggests that paeonol improves renal and vascular AT1R functions by inhibition of oxidative stress, thus lowering blood pressure in SHRs.
Introduction
Hypertension is an important risk factor for coronary heart disease, stroke, chronic renal insufficiency, etc (Citation1,Citation2). Relevant survey data show that in China, the prevalence of hypertension among residents over the age of 18 is 18.8%, and it is estimated that there are more than 200 million people in the country (Citation3). Although the research on hypertension has made remarkable achievements, the etiology is still unclear. Therefore, clarifying the pathogenesis of hypertension is of great significance to its prevention and treatment.
Blood vessels and kidneys are the most important organs for controlling blood pressure (Citation4). Vasoconstriction and diastolic function, and renal sodium excretion disturbance are one of the most direct causes of hypertension (Citation5,Citation6). In recent years, the role of the renin-angiotensin system in the development of hypertension has attracted extensive attention (Citation7). RAS increases blood pressure mainly by promoting vasoconstriction and promoting renal sodium reabsorption (Citation8). Studies have found that the expression and function of angiotensin II type 1 receptors (AT1R) are upregulated in the blood vessels and kidneys of spontaneously hypertensive rats (Citation9,Citation10) which may be one of the important reasons for the occurrence of hypertension.
Although the mechanism of changes in AT1R expression and function in hypertension remains to be elucidated, studies have shown that increased oxidative stress plays an important role in this process (Citation11,Citation12). Oxidative stress leads to AT1R upregulation, which in turn causes overstimulation of sodium transporters and subsequently contributes to sodium retention and hypertension in old (Citation13) and obese Zucker rats (Citation14). In addition, oxidative stress can also promote Ang II-induced contraction response in mesenteric arteries (Citation15). Conversely, antioxidative stress treatment restores AT1R function and reduces blood pressure in old rats (Citation16) and SHRs (Citation17), indicating there is a causal link between oxidative stress and related changes in blood pressure and AT1R function. Paeonol is extracted from Moutan Cortex. As a traditional Chinese medicine, it has antioxidant (Citation18), anti-tumor (Citation19), and atherosclerotic (Citation20) effects. Despite these pharmacological findings, the possible role of paeonol in improving AT1R function has yet to be elucidated. Therefore, in the present study, we hypothesized that paeonol improves renal and vascular AT1R functions and lowers blood pressure via inhibiting oxidative stress in SHRs.
Materials and methods
Animal protocols
Male WKY rats and SHRs (16 weeks) were purchased from Vital River Laboratory Animal Technology in Beijing, China. This study was conformed to the National Institutes of Health guidelines and the protocols were approved by the Committee on Animal Care of Guizhou University of Chinese Medicine. Animals had free access to standard rodent chow and drinking water. WKY rats and SHRs were randomly divided into control and paeonol treatment groups. Control group continued with regular drinking water and the treatment group was provided with paeonol (5 g/kg/day; Sigma, St. Louis, MO) dissolved in drinking water for 5 weeks.
Blood pressure and body weight measurement
Blood pressure and heart rate were measured once weekly for 5 weeks using a CODA noninvasive tail-cuff system (BP-98A; Softron, Tokyo, Japan). Before the measurement, the rats were placed on a heating blanket at 37°C, and the rat tail was heated for 5 min. Meanwhile, it was necessary to ensure that the rats were awake and in a quiet environment. Blood pressure was measured 3 times and the average value was taken. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were recorded. In addition, body weight was measured at 21 weeks of age.
Analysis of oxidative stress and some peptide concentration
To assess the level of oxidative stress, the superoxide dismutase (SOD) and lipid peroxidation product malondialdehyde (MDA) in kidney were measured by using a commercial kit (Beyotime Institute of Biotechnology, Shanghai, China). The glutathione (GSH) and MDA levels in vascular tissue were measured by using a commercial kit (Beyotime Institute of Biotechnology, Shanghai, China). Renin activity in the renal cortex was quantified by a commercially available radioimmunoassay kit and Ang II concentrations in plasma were measured by using enzyme immunoassay kit (Cloud Clone, Wuhan, China).
Animal surgery and renal function studies
Renal function was determined by adrenal artery perfusion surgery, as reported in previous study (Citation21). In brief, the rats were weighed and anesthetized with pentobarbital (50 mg/kg body wt, intraperitoneally). A PE-240 catheter was inserted into the trachea to assist breathing. The jugular vein was placed into PE-50 tubes (infusion tube) and PE-10 tube (anesthesia tube). A PE-50 tube was placed in the right carotid artery to monitor changes in blood pressure and heart rate. Opening the abdominal cavity and looking for the adrenal artery, cutting, and inserting a PE-10 tube for the infusion of solvents or drugs. Finally, the left and right ureters were exposed, and PE-10 tubes were cut and inserted to collect urine. One hour after the operation, the solvent or drug was perfused through the right adrenal artery. The experiment was divided into 3 stages, which were basal period (physiological saline), experimental period (AT1R antagonist candesartan, 10 μg/kg/min), and recovery period (physiological saline). The collection time was 45 min in each period. Urine flow and urinary sodium excretion (UNaV) were recorded for each period.
Preparation and study of mesenteric arteries
The study of mesenteric artery ring was performed according to previous reports (Citation22). In brief, third-order branches of the superior mesenteric artery were cut into rings (2 mm), and mounted on 40 μm stainless-steel wires in a multi myograph system to measure the isometric tension. The rings were maintained in PSS at 37°C with oxygen (95%) and carbon dioxide (5%). After a 45-min equilibration period, the mesenteric artery rings were exposed to 120 mM KCl to assess their functional integrity. The concentration-response curves to Ang II (10−9-10−5M, Sigma Aldrich) were constructed. The mesenteric artery rings were incubated with candesartan (AT1R antagonist, 10 μM, Sigma Aldrich) for 30 min before phenylephrine (PHE, 10−9-10−5M, Sigma Aldrich) was added to induce contraction.
Western blot analysis
The protein expressions of AT1R in the kidney and mesenteric arteries were determined by western blot, as reported in previous studies (Citation23). In brief, the kidney cortexes and mesenteric arteries were homogenized using ice-cold RIPA lysis buffer. Equal amounts of proteins (50 μg) were separated by SDS-PAGE and transferred onto nitrocellulose membranes. The blots were incubated with primary polyclonal antibodies for anti-ACE, anti-AT1R and anti-GAPDH (1:500, Santa Cruz Biotechnology, Santa Cruz, CA, USA) at 4°C overnight. The membranes were washed and incubated with anti-rabbit secondary antibody (1:10000, Li-Cor Biosciences, NE, USA) for 1 h at room temperature. The bound complex was detected using the Odyssey Infrared Imaging System and the images were analyzed using Quantity One software.
Statistical analysis
The data are expressed as mean ± SEM. Statistical analysis was carried out using the Graphpad Prism 5.0 software. Data were analyzed by one-way or two-way ANOVA followed by Newman-keuls post hoc test whenever appropriate. Value of P < .05 was considered significant.
Results
Paeonol lowers blood pressure in SHRs
To determine whether paeonol can reduce blood pressure in SHRs, WKY rats and SHRs were treated with paeonol for 5 weeks. Our results showed that paeonol treatment lowered SBP and DBP in SHRs (), but had no effect on the blood pressure in WKY rats and the heart rate in WKY rats and SHRs (). In addition, in order to exclude the effect of body weight on blood pressure, we measured the body weight of rats after paeonol treatment. There was no significant difference in body weight among all groups, suggesting that paeonol had no effect on body weight ().
Figure 1. Effect of paeonol on lowering blood pressure in SHRs. The WKY rats and SHRs were treated with vehicle or paeonol (5 g/kg/day) for 5 weeks. Systolic blood pressure (SBP) (a) and diastolic blood pressure (DBP) (b) were measured from 16 to 21 weeks of age by tail-cuff plethysmography. Data are expressed as the means ± S.E.M (n = 6/group). *P < .05 vs WKY; #P < .05 vs SHR. (c and d) Heart rate measurement by tail-cuff plethysmography and body weight measurement in 21-week-old rats.
Paeonol reduces renal and vascular oxidative stress in SHRs
The antioxidant capacity as SOD level was lower in kidney from SHRs than WKY rats. Paeonol treatment increased the antioxidant capacity in SHRs (). However, Paeonol treatment did not change the antioxidant capacity in WKY rats (). The renal MDA levels were significantly higher in SHRs compared with WKY rats. Treatment with Paeonol reduced the levels of renal MDA in SHRs (). However, Paeonol treatment did not change the renal MDA levels in WKY rats. In addition, we measured MDA and GSH levels in vascular tissue in different groups, and found that MDA levels were increased and GSH levels were decreased in SHRs, which were reversed by paeonol treatment ().
Figure 2. Effect of paeonol on renal and vascular oxidative stress from WKY rats and SHRs. The indices of oxidative stress included renal superoxide dismutase (SOD) (a) malondialdehyde (MDA) (b), and vascular MDA (c) and glutathione (GSH). The WKY rats and SHRs were treated with vehicle or paeonol (5 g/kg/day) for 5 weeks. Data are expressed as the means ± S.E.M (n = 6/group). *P < .05 vs WKY; #P < .05 vs SHR.
Paeonol improves renal AT1R function in SHRs
To determine the effect of paeonol on renal AT1R function in WKY rats and SHRs, AT1R antagonist candesartan was perfused through the adrenal artery to observe diuretic and natriuretic effects. These results showed that there was a significantly greater increase in urine flow in response to the AT1R antagonist candesartan in SHRs. Similarly, there was an exaggerated response to candesartan on UNaV in SHRs than in WKY rats (). Although paeonol treatment had no effect in WKY rats, the exaggerated diuretic and natriuretic responses to candesartan were reduced with paeonol treatment in SHRs.
Figure 3. Effect of paeonol on renal AT1R function in WKY rats and SHRs. The WKY rats and SHRs were treated with vehicle or paeonol (5 g/kg/day) for 5 weeks. Urine flow (a) and urinary sodium excretion (UNaV) (b) were recorded during the vehicle or candesartan (10 ug/kg/minute) infusion via the right suprarenal artery of rats. Data are expressed as the means ± S.E.M (n = 6/group). *P < .05 vs respective basal using repeated-measures ANOVA followed Newman-keuls post hoc test; #P < .05 vs WKY within the same treatment and $P < .05 vs SHR within the same treatment using one-way ANOVA followed by Newman-keuls post hoc test.
Paeonol improves vascular AT1R function in SHRs
Due to the important role of vascular contraction in the regulation of blood pressure, vascular reactivity was measured. AT1R agonist Ang II-induced contraction of mesenteric arteries was stronger in SHRs than in WKY rats, indicating that SHRs had stronger vascular AT1R function. Treatment with paeonol reduced Ang II-induced contraction of mesenteric arteries in SHRs (). However, paeonol treatment did not change Ang II-induced contraction of mesenteric arteries in WKY rats. To further determine the effect of paeonol on vascular AT1R function, the effect of the selective AT1R antagonist Candesartan on the concentration-response curve to phenylephrine in mesenteric rings from WKY rats and SHRs was observed. Our results found that Candesartan reduced the vasoconstrictor response induced by phenylephrine in mesenteric arteries from SHRs but not in SHRs with paeonol treatment and WKY rats (), suggesting vascular AT1R function in SHRs was enhanced, paeonol treatment reduced vascular AT1R function in SHRs.
Figure 4. Effect of paeonol on vascular AT1R function in WKY rats and SHRs. The WKY rats and SHRs were treated with vehicle or paeonol (5 g/kg/day) for 5 weeks. (a) Ang II-induced contraction in mesenteric arteries from WKY rats and SHRs. (b and c) Effect of preincubation with candesartan on the concentration-response curve to phenylephrine in mesenteric arteries from WKY rats and SHRs. Data are expressed as the means ± S.E.M (n = 6/group). *P < .05 vs others, one-way ANOVA followed by Newman-keuls post hoc test.
Paeonol reduces renal and vascular ACE and AT1R expression in SHRs
Because paeonol modified the effect AT1R mediated renal natriuresis and vascular contraction in SHRs, we determined if those effects were accompanied by changes in renal and vascular AT1R protein expression. We found that the basal expression of renal and vascular ACE and AT1R were higher in SHRs than WKY rats. Paeonol treatment decreased the expression of renal and vascular ACE and AT1R, but not in WKY rats (). Furthermore, we also measured the levels of`renal renin and Ang II in plasma in all groups. We found that compared with WKY rats, renal renin concentrations was lower, while Ang II in plasma was higher in SHR. Paeonol treatment reversed the abnormality of renin and Ang II in SHR ().
Figure 5. Effect of paeonol on the protein expressions of renal and vascular ACE and AT1R in WKY rats and SHRs. The WKY rats and SHRs were treated with vehicle or paeonol (5 g/kg/day) for 5 weeks. Renal (a) and vascular (b) ACE and AT1R protein expressions were determined by immunoblotting. Data are expressed as the means ± S.E.M (n = 6/group). *P < .05 vs WKY; #P < .05 vs SHR.
Figure 6. Effect of paeonol on the levels of renin in kidney and Ang II in plasma in WKY and SHRs. The WKY rats and SHRs were treated with vehicle or paeonol (5 g/kg/day) for 5 weeks. The levels of renin in kidney (a) and Ang II in plasma (b) were determined by immunoassay kit. Data are expressed as the means ± S.E.M (n = 6/group). *P < .05 vs WKY; #P < .05 vs SHR.
Discussion
Hypertension is an independent risk factor for cardiovascular and cerebrovascular diseases such as acute myocardial infarction, stroke, and heart failure (Citation24,Citation25). Since sodium retention and enhanced vasoconstriction are the hallmark of essential hypertension, a growing number of studies have focused on abnormal renal sodium handling and vasoconstriction in the pathogenesis of hypertension (Citation26,Citation27). AT1R, as an important component of RAS, is an important regulator of sodium homeostasis, vasoconstriction and relaxation, and blood pressure (Citation28). We showed a causal link between oxidative stress and renal and vascular AT1R function, because antioxidant paeonol treatment restored renal and vascular AT1R function and reduced blood pressure in SHRs. The objective of the current study was to investigate the biochemical mechanisms by which paeonol treatment may reduce oxidative stress, alter renal and vascular AT1R function, leading to a decrease in blood pressure in SHRs.
Renal RAS plays an important role in maintaining the balance of urinary sodium and blood pressure in the body (Citation29). Changes in the expression and activity of RAS components, especially AT1R, are involved in the occurrence and development of many cardiovascular diseases, including hypertension (Citation30). Ang II is a major RAS component that mediates antidiuretic and vasoconstrictive effects by acting on AT1R, thereby promoting the elevation of blood pressure (Citation31). Previous studies have shown that the expression of renal AT1R is upregulated in the rat animal model of essential hypertension, and it is mainly expressed in the renal proximal tubule epithelium, which can promote the reabsorption of urinary sodium by enhancing the activity of sodium hydrogen exchanger (Citation32,Citation33). In this study, we found that diuretic and natriuretic responses to candesartan (AT1 receptor antagonist), and renal AT1R expression were higher in SHRs compared with WKY rats. These changes in sodium excretion in response to candesartan suggest an exaggerated renal AT1R function in SHRs. In addition, our study in small resistance arteries revealed that Ang II induced a stronger vasoconstrictor response in mesenteric arteries from SHRs than WKY rats, which might be ascribed to the upregulated AT1R expression in mesenteric arteries from SHRs.
The mechanism of enhanced renal and vascular AT1R function in SHRs is not known. There is emerging evidence that oxidative stress contributes to an increase in blood pressure in various animal models of hypertension (Citation34,Citation35). Previous studies reported a causal role of oxidative stress in diminished dopamine D1R-mediated natriuretic response, exaggerated AT1R-mediated antinatriuretic response, and high blood pressure in old rats (Citation16) and Zucker obese rats (Citation36,Citation37). Antioxidant treatment reduces blood pressure and normalizes the exaggerated diuretic and natriuretic response to candesartan in old rats (Citation38). As a Chinese medicine, it has been proved that paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition oxidative stress (Citation18). Our study found that oxidative stress altered renal and vascular functions, leading to high blood pressure in SHRs. Paeonol treatment in SHRs reduced the candesartan-induced increase in diuresis and urinary sodium excretion and vasoconstriction via inhibiting oxidative stress, which contributed to lower blood pressure.
Regarding exaggerated renal and vascular AT1R function in SHRs, it is likely that oxidative stress increases the expression and function of renal and vascular AT1R. Previous studies show that an increase in oxidative stress in renal proximal tubules is associated with higher NF-κB and GRK4 activity, increased AT1R mRNA levels, and exaggerated AT1R function (Citation39,Citation40). Therefore, it is likely that oxidative stress mediates an increase in AT1R transcription via NF-κB or GRK4 and may represent the mechanism of exaggerated AT1R function in SHRs. However, NF-κB or GRK4 levels still need to be determined in SHRs with paeonol treatment, which will be undertaken in future studies.
To our knowledge, for the first time, we show that paeonol improves renal and vascular AT1R functions through reducing oxidative stress in SHRs. The present study thus provides new mechanistic information underlying the beneficial effects of paeonol to lower blood pressure in hypertension.
Data sharing statement
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request
Author contribution
YW conceived and designed the experiments and wrote the manuscript; YZ performed the experiments and analyzed the data; QH contributed reagents analysis tools; ST approved the final version of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
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