Selenium deficiency causes hypertension by increasing renal AT receptor expression via GPx1/HO/NF-κB pathway

Lifu Lei, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Fuwei Zhang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Juan Huang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Xinyue Yang, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Xiaoxin Zhou, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Hongjia Yan, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Shuo Zheng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Liangyi Si, Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology and Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China. Electronic address: chunyuzeng01@163.com.
Jian Yang, Research Center for Metabolic and Cardiovascular Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: jianyang@hospital.cqmu.edu.cn.

Document Type

Journal Article

Publication Date

5-1-2023

Journal

Free radical biology & medicine

Volume

200

DOI

10.1016/j.freeradbiomed.2023.02.021

Keywords

Angiotensin II type 1 receptor; Hypertension; Kidney; Oxidative stress; Selenium deficiency

Abstract

Epidemiological studies show an association between low body selenium and the risk of hypertension. However, whether selenium deficiency causes hypertension remains unknown. Here, we report that Sprague-Dawley rats fed a selenium-deficient diet for 16 weeks developed hypertension, accompanied with decreased sodium excretion. The hypertension of selenium-deficient rats was associated with increased renal angiotensin II type 1 receptor (ATR) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the ATR antagonist candesartan. Selenium-deficient rats had increased systemic and renal oxidative stress; treatment with the antioxidant tempol for 4 weeks decreased the elevated blood pressure, increased sodium excretion, and normalized renal ATR expression. Among the altered selenoproteins in selenium-deficient rats, the decrease in renal glutathione peroxidase 1 (GPx1) expression was most prominent. GPx1, via regulation of NF-κB p65 expression and activity, was involved in the regulation of renal ATR expression because treatment with dithiocarbamate (PDTC), an NF-κB inhibitor, reversed the up-regulation of ATR expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of ATR expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal ATR expression, Na-K-ATPase activity, hydrogen peroxide (HO) generation, and the nuclear translocation of NF-κB p65 protein in selenium-deficient RPT cells. Our results demonstrated that long-term selenium deficiency causes hypertension, which is due, at least in part, to decreased urine sodium excretion. Selenium deficiency increases HO production by reducing GPx1 expression, which enhances NF-κB activity, increases renal ATR expression, causes sodium retention and consequently increases blood pressure.

Department

Medicine

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