Inhibition of endoplasmic reticulum stress restores the balance of renal RAS components and lowers blood pressure in the spontaneously hypertensive rats

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.

KEYWORDS:

• Endoplasmic reticulum stress
• hypertension
• Renin-angiotensin system
• Oxidative stress
• kidney

Disclosure statement

No potential conflict of interest was reported by the authors.

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.

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

The work was supported in part by grants from the Project of Chongqing Technology Innovation and Application Demonstration Special Social and People’s Livelihood Key Research and Development (cstc2018jscx-mszd0082).