ABSTRACT
Background
Endoplasmic reticulum (ER) stress has been shown to play a critical role in the pathogenesis of hypertension. However, the underlying mechanisms for lowering blood pressure (BP) by suppressing ER stress remain unclear. Here, we hypothesized that inhibition of ER stress could restore the balance between RAS components and lower BP in spontaneously hypertensive rats (SHRs).
Methods
Wistar-Kyoto (WKY) rats and SHRs received vehicle or 4-PBA, an ER stress inhibitor, in the drinking water for 4 weeks. BP was measured by tail-cuff plethysmography, and the expression of RAS components was examined by Western blot.
Results
Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure and increased renal ER stress and oxidative stress, accompanied by impaired diuresis and natriuresis. Moreover, SHRs had higher ACE and AT1R and lower AT2R, ACE2, and MasR expressions in the kidney. Interestingly, 4-PBA treatment improved impaired diuresis and natriuresis and lowered blood pressure in SHRs, accompanied by reducing ACE and AT1R protein expression and increasing AT2R, ACE2, and MasR expression in the kidneys of SHRs. In addition, these changes were associated with the reduction of ER stress and oxidative stress.
Conclusions
These results suggest that the imbalance of renal RAS components was associated with increased ER stress in SHRs. Inhibition of ER stress with 4-PBA reversed the imbalance of renal RAS components and restored the impaired diuresis and natriuresis, which, at least in part, explains the blood pressure-lowering effects of 4-PBA in hypertension.
Introduction
At present, hypertension and its complications are the leading cause of death and burden of disease globally, according to the World Health Organization, which have become major public health problems affecting the economic and social development of most countries in the world (Citation1). Although great achievements have been made, the control of hypertension is still unsatisfactory. The unclear pathogenesis of hypertension is the main factor restricting its prevention and treatment. Therefore, there is an urgent need to deeply explore the new pathogenesis of hypertension and find effective treatment targets.
In regulation system of blood pressure, the renin–angiotensin system (RAS) plays an important role (Citation2). The RAS is divided into classical pathways (renin/angiotensin/angiotensin type I receptor) and non-classical pathways (renin/angiotensin/angiotensin type II receptor and renin/Ang (Citation1–7)/Mas receptor) (Citation3). The two pathways antagonize each other and jointly regulate and maintain the stability of blood pressure (Citation4). Angiotensin II is a major RAS-active peptide that exerts its effects by binding to angiotensin type I receptor (AT1R) and angiotensin type II receptor (AT2R) (Citation5). Binding to AT1R can mediate vasoconstriction (Citation6) and renal sodium retention (Citation7), thereby promoting the elevation of blood pressure. However, binding to AT2R can mediate vasodilation and renal natriuretic effect and promote the reduction of blood pressure (Citation8). In addition, the activation of Mas receptors in the non-canonical pathway of RAS can also promote vasodilation and renal natriuresis, thereby functionally antagonizing the vasopressor effect of the classical pathway (Citation9). Previous studies have shown that the imbalance between the classical and non-canonical pathways of renal RAS can lead to the disturbance of renal natriuresis, which in turn leads to an increase in blood pressure (Citation10,Citation11).
Although the mechanism of the imbalance of renal RAS components in hypertension remains to be elucidated, studies have confirmed that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of hypertension (Citation12). ER is an organelle responsible for protein folding and assembly and participates in many physiological functions. When ER homeostasis is perturbed, ER function is impaired, which leads to activation of unfolded protein responses to restore cellular homeostasis (Citation13). However, the long-term accumulation of unfolded proteins in the endoplasmic reticulum triggers ER stress, which can trigger the activation of apoptosis, inflammation, and oxidative stress (Citation14). More evidence shows that ER stress is related to the occurrence and development of diseases, such as hypertension (Citation15), atherosclerosis (Citation16), and malignant tumors (Citation13). Inhibition of ER stress improves endothelial function and lowers blood pressure in spontaneously hypertensive rats (SHR) (Citation17) and the offspring of dams with diabetes (Citation18). To date, no study has examined the role of ER stress in the imbalance of renal RAS components in hypertension. Therefore, the present study investigated whether renal RAS components in SHRs are imbalanced and treatment of ER stress inhibitors could restore the balance of renal RAS components and lower the elevated blood pressure in SHRs.
Materials and methods
Animal protocols
Male WKY and SHRs were purchased from Vital River Laboratory Animal Technology in Beijing, China. This study was approved by the Committee on Animal Care at Army Medical University. The procedures were conformed to the NIH guidelines for the care and use of laboratory animals. All the rats were housed in a temperature-controlled room with a 12-h light cycle and had access to food and water ad libitum. WKY and SHRs were randomly divided into control and 4-PBA treatment group. Control group continued on regular drinking water, and the treatment group was provided with 4-PBA (1 g/kg/day; Sigma, St Louis, MO) dissolved in the drinking water for 4 weeks.
Blood pressure measurement
To ensure the stability of the measurements, the rats were trained for 3 days to adapt to the measurement process. Indirect systolic blood pressure and heart rate were measured once weekly for 4 weeks using a CODA noninvasive tail-cuff system (BP-98A; Softron, Tokyo, Japan).
Urine analysis and creatinine measurement
Urine was collected in metabolic cages for 24 h in the last week. Urine volumes were measured for 24 h, and sodium excretions were analyzed using a flame photometer 480 (Ciba Corning Diagnostics, Norwood, MA). Creatinine levels in serum and urine were measured by a creatinine analyzer (Beckman, Fullerton, CA). The glomerular filtration rate (GFR) (milliliters per minute) was calculated from creatinine clearance.
Biochemical markers of oxidative stress
To assess the level of oxidative stress, the superoxide dismutase (SOD) and lipid peroxidation product malondialdehyde (MDA) in the renal cortex were measured using a commercial kit (Beyotime Institute of Biotechnology, Shanghai, China).
Some peptide concentration
Ang II concentrations in the renal cortex were measured using enzyme immunoassay kit (Cloud Clone, Wuhan, China), and aldosterone concentrations in serum were measured using a commercially available radioimmunoassay kit (DiaSorin, Dietzenbach, Germany).
Western blot analysis
The protein expressions of RAS components were determined by western blot, as reported in previous studies (Citation7). In brief, the kidney cortexes were homogenized using an ice-cold RIPA lysis buffer. The equal amounts of proteins (100 ug) were separated by SDS-PAGE and transferred onto nitrocellulose membranes. The blots were incubated with primary polyclonal antibodies for anti-GRP78, activating transcription factor 6 (ATF6) (1:400; Cell Signaling Technology, Danvers, MA, USA), anti-AT1R, anti-ACE, anti-AT2R, anti-ACE2, and anti-GAPDH (1:500, Santa Cruz Biotechnology, Santa Cruz, CA, USA), and anti-MasR (1:500; Alomone Labs Ltd, Jerusalem, Israel) at 4°C overnight. The membranes were washed with phosphate buffered saline with Tween 20 and were incubated with secondary antibodies 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.
Cell culture
In vitro experiments utilized primary cultures of renal proximal tubule (RPT) cells from WKY rats and SHRs. RPTs were isolated as described previously (Citation10). RPT cells were cultured at 37°C in 95% air and 5% CO2 using DMEM/F12 with 10% FBS, epidermal growth factor (10 ng/mL), insulin (0.573 ng/mL), and penicillin (25 IU/mL). The RPT cells (95% confluence) were serum-deprived for 2 h and then treated with vehicle, 4-PBA (1 mmol/L), alone, or in combination for 24 h. The total RNA was extracted from treated cells to determine the mRNA levels of RAS components.
Real-time quantitative PCR analysis
Total RNA from RPT was isolated using TRIzol reagent and synthesized cDNA using specific primers, listed in . qRT-PCR was performed using the CFX96 Touchtm Real-Time PCR Detection System (Bio-Rad). Gene expression was measured by the DDCT method and normalized to GAPDH mRNA expression. The data are presented as a fold-change of the gene of interest, relative to that of the control group.
Table 1. List of primers used for quantitative real-time RT-PCR.
Statistical analysis
Data are expressed as mean ± SEM. Data were analyzed by one-way ANOVA followed by Newman–Keuls post hoc test. A value of P < .05 was considered significant.
Results
Inhibition of ER stress with 4-PBA improves impaired renal function and lowers blood pressure in SHRs
To determine whether ER stress inhibitor (4-PBA) can reduce blood pressure in SHRs, the rats were treated with 4-PBA (1 g/kg/day) dissolved in the drinking water for 4 weeks. Our results showed that 4-PBA treatment lowered SBP in SHRs but had no effect on blood pressure in WKY rats (). Meanwhile, there was no difference in average heart rate over 4 weeks among all groups (). The decreased SBP in SHRs with 4-PBA treatment, at least in part, is due to the improvement in renal function because 4-PBA treatment increased urine volume and sodium excretion for 24 h () and reduced creatinine in serum and increased GFR ().
Figure 1. Effect of the ER stress inhibition on blood pressure and heart rate in WKY rats and SHRs. (a) Blood pressure was measured from 13 to 17 weeks of age by tail-cuff plethysmography. (b) Average heart rate was measured among all groups. Data are expressed as the means ± S.E.M (n = 6/group). *P<.05 vs. WKY; #P<.05 vs. SHR.
Figure 2. Effect of the ER stress inhibition on the regulation of renal function in WKY rats and SHRs. The WKY rats and SHRs were treated with vehicle or 4-PBA (1 g/kg/day) for 4 weeks. 24 h urine volume (a) and sodium excretion (b) were determined by metabolic cages, and creatinine levels in serum (c) were measured by a creatinine analyzer and GFR (d) was calculated from creatinine clearance in WKY rats and SHRs at the age of 17 weeks. Data are expressed as the means ± S.E.M (n = 6/group). *P<.05 vs. others.
Effect of ER stress inhibition on renal RAS components in SHRs
Because 4-PBA treatment improves renal natriuresis in SHRs, we determined if the effect was accompanied by changes in renal protein expressions of RAS components. We found that compared to WKY, the basal expressions of ACE and AT1R were higher, while AT2R, ACE2, and MasR expressions were lower in SHRs (), indicating that there was an imbalance of the renal RAS components in SHRs. ER stress inhibitor (4-PBA) treatment for 4 weeks decreased the renal ACE and AT1R expressions, increased AT2R, ACE2, and MasR expressions in SHRs (), suggesting that the inhibition of ER stress can improve the imbalance of RAS components in SHRs. In addition, we also measured the renal Ang II and serum aldosterone concentrations and found that compared with WKY, renal Ang II and serum aldosterone concentrations were higher in SHR. ER stress inhibitor (4-PBA) treatment for 4 weeks decreased renal Ang II and serum aldosterone concentrations in SHR (). To determine the direct effect of 4-PBA on RAS components, we treated primary cultures of RPT cells from WKY rats and SHRs with 4-PBA (1 mmol/L) for 24 h. Our results showed that treatment of RPT cells from SHRs with 4-PBA decreased the renal ACE and AT1R mRNA levels, increased AT2R, ACE2, and MasR mRNA (). All the results in vitro are in agreement with in vivo studies.
Figure 3. Effect of the ER stress inhibition on renal RAS components in WKY rats and SHRs. The WKY rats and SHRs were treated with vehicle or 4-PBA (1 g/kg/day) for 4 weeks. (a-e) Those protein expressions of RAS components including ACE, AT1R, AT2R, ACE2, and MasR were determined by immunoblotting in WKY rats and SHRs at the age of 17 weeks. (f and g) the concentrations of Ang II in renal cortex and serum aldosterone were measured using immunoassay kit. Data are expressed as the means ± S.E.M (n = 6/group). *P<.05 vs. others.
Figure 4. Effect of the ER stress inhibition on the mRNA levels of RAS components in primary cultures of RPT cells from WKY rats and SHRs. The RPT cells were treated with vehicle or 4-PBA (1 mmol/L) for 24 h. (A) mRNA expressions of RAS components including ACE, AT1R, AT2R, ACE2, and MasR were determined by qRT-PCR. Data are expressed as the means ± S.E.M (n = 6/group). *P<.05 vs. WKY; #P<.05 vs. SHR.
ER stress inhibition ameliorates ER stress associated oxidative stress in SHRs
Disruption of normal ER stress is accompanied by increased blood pressure (Citation19). We found that the expressions of ER stress markers, including GRP78 and ATF6, were increased in SHRs compared with WKY, which were reversed by the treatment with ER stress inhibitor (4-PBA) in SHRs (). ER stress has been reported to initiate a burst of oxidative stress. To further determine the role of oxidative stress in WKY rats and SHRs, we measured MDA, an index of lipid peroxidation, and SOD, an antioxidant, levels in the kidney cortex. The renal cortical level of MDA was higher and SOD was lower in SHRs than in WKY rats (), indicating that oxidative stress increased in SHRs. Treatment with 4-PBA for 4 weeks in SHRs reduced the increased oxidative stress (), which was accompanied by restoring the balance of RAS components, increasing 24 h urine volume and sodium excretion, and lowering blood pressure.
Figure 5. Effect of the ER stress inhibition on the ER stress and oxidative stress markers in renal cortex of WKY rats and SHRs. The WKY rats and SHRs were treated with vehicle or 4-PBA (1 g/kg/day) for 4 weeks. (a and b) Those protein expressions of ER stress markers including GRP78 and ATF6 were determined by immunoblotting. (c and d) Oxidative stress markers including malondialdehyde (MDA) and SOD were measured using a commercial kit. Data are expressed as the means ± S.E.M (n = 6/group). *P<.05 vs. others.
Discussion
Recent studies have shown that the activation of ER stress signaling pathways is closely related to the occurrence and development of hypertension (Citation20). Inhibition of ER stress can stabilize protein conformation and promote the transfer of unfolded or misfolded proteins out of the endoplasmic reticulum (Citation21), suggesting that inhibiting ER stress signaling may be an important target for hypertension treatment (Citation22). The mechanisms by which ER stress contributes to hypertension are still being investigated. In the present study, we found that ER stress contributes to impaired natriuresis and diuresis in hypertension. The main findings of this study are as follows: (Citation1) ER stress inhibitor, 4-PBA, decreased blood pressure in SHRs; (Citation2) natriuretic function was impaired in SHRs and inhibition of ER stress improved renal sodium excretion function; (Citation3) renal RAS components were imbalance in SHRs, which were restored by treatment of 4-PBA; and (Citation4) 4-PBA decreased ER stress and oxidative stress, which was associated with the improvement of imbalance of renal RAS components in SHRs. These results suggest that increased ER stress is responsible for the imbalance of renal RAS components and impaired natriuresis and diuresis in SHRs, which were restored by 4-PBA treatment.
In hypertensive patients and animal models, there is a phenomenon of urinary sodium retention in the body, which can further promote the occurrence and development of hypertension (Citation23,Citation24). Previous studies have shown that in the hypertensive state, the regulation of blood pressure is closely related to the dysfunction of renal sodium excretion (Citation25). RAS is one of the most important systems for regulating water and sodium balance in the body (Citation26). The RAS system is divided into classical and non-classical pathways. The classical pathway (renin/angiotensin II/AT1R) plays a positive role in regulating blood pressure, while the non-classical pathway (renin/angiotensin II/AT2R or renin/Ang (Citation1–7)/MasR) plays a negative role in regulating blood pressure (Citation27). A normal balance between classical and non-classical pathway keeps sodium excretion and blood pressure in the normal range (Citation28). However, in hypertensive states, that balance is lost (Citation29). Previous studies have shown that in the hypertensive rat model, the classical pathway of RAS in the central blood pressure regulation system (supraventricular nucleus and paraventricular nucleus) is significantly upregulated, while the non-classical pathway is downregulated, which promotes increase in blood pressure (Citation30). Moreover, the imbalance of renal RAS components is one of the most important pathogenesis of obesity-related hypertension, and restoring the balance of renal RAS components can improve renal sodium excretion and reduce blood pressure in obese Zucker rats (Citation10). In our present study, we found that there was an imbalance of renal RAS components and impaired natriuresis and diuresis in SHRs. However, the underlying mechanism of the imbalance of renal RAS components in SHRs is still not clear.
Extensive evidence suggests that pathogenesis of hypertension is closely related to the increase in ER stress level (Citation31). ER stress is mainly manifested by an increase in the level of unfolded proteins, which can reduce the bioavailability of nitric oxide in the vascular endothelium, impair the function of the arterial endothelium (enhanced vasoconstriction and reduced vasodilation), and promote vascular remodeling (increased media-to-lumen ratio) (Citation32,Citation33). Furthermore, ER stress can promote the increase in the level of oxidative stress, which leads to the activation of sympathetic nerves, resulting in an increase in blood pressure (Citation34). ER stress initiates a burst of oxidative stress in the ER lumen and by targeting the mitochondria, triggers the elevation of cytosolic Ca2+ and reactive oxygen species, supporting a causal link between ER stress and its downstream activation of oxidative stress (Citation35). ER stress inhibition significantly reverses increased oxidative stress, reduces the media-to-lumen ratio and vasoconstrictor responses, and improves vasodilatory response in resistant arteries from SHRs (Citation36). Inhibition of ER stress with 3-hydroxy-2-naphthoic acid can attenuate Ang II-induced vascular remodeling and hypertension (Citation37). In our present study, ER stress markers including GRP78 and ATF6, and oxidative stress were upregulated in the kidney cortexes of SHRs. 4-PBA treatment blunted the expression of GRP78 and ATF6 and reduced oxidative stress in SHRs. Previous studies have shown that amelioration of oxidative stress restores the balance between the natriuretic and antinatriuretic components of the renal RAS increases sodium excretion and reduces blood pressure in obesity-related hypertension (Citation10). We found that inhibition of ER stress with 4-PBA reduced oxidative stress, restored the balance of renal RAS components, and lowered blood pressure in SHRs.
The major limitation of our study is that the improvement of oxidative stress in SHRs treated with 4-PBA may be secondary to the systemic administration of ER stress inhibitors because the improvement of ER stress can reduce the body’s inflammatory response (Citation38) and activate autophagy (Citation39), and so on, all of which can promote the improvement of oxidative stress. Thus, it is not clear whether 4-PBA have a primary effect on the reduction of oxidative stress in SHRs. Despite the limitations of this study, this is the first study to show the effect of ER stress inhibition in restoring the balance of RAS components in SHRs. Moreover, we showed which ER stress is related to the imbalance of RAS components and consequent high blood pressure in SHRs. Thus, our present study may provide a new approach for the treatment of hypertension.
Author contribution
J.Z. and A.S. designed the experiments and performed the data acquisition; C.W., D.H., and C. Z. performed the data analyses and revision of the manuscript. H.W. drafted the manuscript. All authors revised the manuscript and approved the final version.
Disclosure statement
No potential conflict of interest was reported by the authors.
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
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