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  3. Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-κB pathway

Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-κB pathway

  • Free Radic Biol Med. 2023 Mar 1;S0891-5849(23)00094-1. doi: 10.1016/j.freeradbiomed.2023.02.021.
Lifu Lei 1,  Fuwei Zhang 2,  Juan Huang 1,  Xiaoxin Zhou 1,  Hongjia Yan 1,  Caiyu Chen 3,  Shuo Zheng 3,  Liangyi Si 2,  Pedro A Jose 4,  Chunyu Zeng 5,  Jian Yang 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Clinical Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 36868433 DOI: 10.1016/j.freeradbiomed.2023.02.021
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 (AT1R) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the AT1R 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 AT1R 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 AT1R expression because GPx1 silencing or treatment with dithiocarbamate (PDTC), an NF-κB Inhibitor, reversed the up-regulation of AT1R expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of AT1R expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal AT1R expression, Na+-K+-ATPase activity, hydrogen peroxide (H2O2) 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 H2O2 production by reducing GPx1 expression, which enhances NF-κB activity, increases renal AT1R expression, causes sodium retention and consequently increases blood pressure.

Keywords

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

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