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. 2023 May 1:200:59-72.
doi: 10.1016/j.freeradbiomed.2023.02.021. Epub 2023 Mar 2.

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

Lifu Lei  1 , Fuwei Zhang  2 , Juan Huang  1 , Xinyue Yang  3 , Xiaoxin Zhou  1 , Hongjia Yan  1 , Caiyu Chen  3 , Shuo Zheng  3 , Liangyi Si  4 , Pedro A Jose  5 , Chunyu Zeng  6 , Jian Yang  7
Affiliations

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

Lifu Lei et al. Free Radic Biol Med. .

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 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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Conflict of interest statement

Declaration of competing interest The authors declared there are no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Effect of selenium deficiency in the regulation of blood pressure and sodium excretion in SD rats.
(A) The different serum selenium (Se) levels between SD rats fed a selenium-deficient diet and those fed a selenium-normal diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (B-D) Systolic-(SBP, B), diastolic-(DBP, C) and mean blood pressures (MBP, D) in SD rats fed the selenium-deficient diet for indicated time (*P < 0.05 vs Se-normal, n=5/group). (E, F) 24-hours urine volume (E) and sodium excretion (UNa, F) in SD rats fed the selenium-deficient diet for indicated time (*P < 0.05 vs Se-normal, n=5/group).
Fig. 1.
Fig. 1.. Effect of selenium deficiency in the regulation of blood pressure and sodium excretion in SD rats.
(A) The different serum selenium (Se) levels between SD rats fed a selenium-deficient diet and those fed a selenium-normal diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (B-D) Systolic-(SBP, B), diastolic-(DBP, C) and mean blood pressures (MBP, D) in SD rats fed the selenium-deficient diet for indicated time (*P < 0.05 vs Se-normal, n=5/group). (E, F) 24-hours urine volume (E) and sodium excretion (UNa, F) in SD rats fed the selenium-deficient diet for indicated time (*P < 0.05 vs Se-normal, n=5/group).
Fig. 2.
Fig. 2.. Effect of selenium deficiency on renal AT1R expression and AT1R-mediated function in SD rats.
(A, B) Expression profiles of select receptors in the renal cortex of SD rats fed the selenium (Se)-deficient diet for 16 weeks. Protein expression was evaluated via immunoblotting for AT1R, AT2R, MasR, CCKBR, ETBR, IR, AdipoR2 (A) and dopamine receptors (B). The protein expression was normalized using GAPDH expression (*P < 0.05 vs Se-normal, n=5/group). (C) The mRNA expression of AT1R was determined by qt-PCR in the renal cortex of SD rats fed the selenium-deficient diet for 16 weeks. AT1R mRNA level was normalized using GAPDH expression (*P < 0.05 vs Se-normal, n=5/group). (D, E) The angiotensin II levels in serum (D) and renal cortex (E) in SD rats fed the selenium-deficient diet for 16 weeks (n=5/group). (F, G) Effect of candesartan (1, 5 or 10 μg/kg/min) on the urine flow (F) and urinary sodium excretion (G) in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, #P < 0.05 vs basal Se-deficiency, n=5/group). (H) The activity of GSH-Px in RPT cells with selenium-free incubation for 24 or 48 hours (*P < 0.05 vs the time 0, n=5/group). (I, J) The mRNA (I) and protein expression (J) of AT1R in selenium-free incubated RPT cells (Se-) and selenium-replete cells (Se+) for 48 hours. AT1R mRNA and protein levels were normalized using GAPDH (*P < 0.05 vs Se+, n=4–5/group). (K) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells from normotensive WKY rats. Cells were incubated with selenium-free media for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal, n=5; #P < 0.05 vs Ang II in Se+ group, n=5/group). (L) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells from Agtr1−/ mice. Cells were incubated with selenium-free media for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs control; #P < 0.05 vs Ang II in Se+ group, n=6/group).
Fig. 2.
Fig. 2.. Effect of selenium deficiency on renal AT1R expression and AT1R-mediated function in SD rats.
(A, B) Expression profiles of select receptors in the renal cortex of SD rats fed the selenium (Se)-deficient diet for 16 weeks. Protein expression was evaluated via immunoblotting for AT1R, AT2R, MasR, CCKBR, ETBR, IR, AdipoR2 (A) and dopamine receptors (B). The protein expression was normalized using GAPDH expression (*P < 0.05 vs Se-normal, n=5/group). (C) The mRNA expression of AT1R was determined by qt-PCR in the renal cortex of SD rats fed the selenium-deficient diet for 16 weeks. AT1R mRNA level was normalized using GAPDH expression (*P < 0.05 vs Se-normal, n=5/group). (D, E) The angiotensin II levels in serum (D) and renal cortex (E) in SD rats fed the selenium-deficient diet for 16 weeks (n=5/group). (F, G) Effect of candesartan (1, 5 or 10 μg/kg/min) on the urine flow (F) and urinary sodium excretion (G) in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, #P < 0.05 vs basal Se-deficiency, n=5/group). (H) The activity of GSH-Px in RPT cells with selenium-free incubation for 24 or 48 hours (*P < 0.05 vs the time 0, n=5/group). (I, J) The mRNA (I) and protein expression (J) of AT1R in selenium-free incubated RPT cells (Se-) and selenium-replete cells (Se+) for 48 hours. AT1R mRNA and protein levels were normalized using GAPDH (*P < 0.05 vs Se+, n=4–5/group). (K) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells from normotensive WKY rats. Cells were incubated with selenium-free media for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal, n=5; #P < 0.05 vs Ang II in Se+ group, n=5/group). (L) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells from Agtr1−/ mice. Cells were incubated with selenium-free media for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs control; #P < 0.05 vs Ang II in Se+ group, n=6/group).
Fig. 2.
Fig. 2.. Effect of selenium deficiency on renal AT1R expression and AT1R-mediated function in SD rats.
(A, B) Expression profiles of select receptors in the renal cortex of SD rats fed the selenium (Se)-deficient diet for 16 weeks. Protein expression was evaluated via immunoblotting for AT1R, AT2R, MasR, CCKBR, ETBR, IR, AdipoR2 (A) and dopamine receptors (B). The protein expression was normalized using GAPDH expression (*P < 0.05 vs Se-normal, n=5/group). (C) The mRNA expression of AT1R was determined by qt-PCR in the renal cortex of SD rats fed the selenium-deficient diet for 16 weeks. AT1R mRNA level was normalized using GAPDH expression (*P < 0.05 vs Se-normal, n=5/group). (D, E) The angiotensin II levels in serum (D) and renal cortex (E) in SD rats fed the selenium-deficient diet for 16 weeks (n=5/group). (F, G) Effect of candesartan (1, 5 or 10 μg/kg/min) on the urine flow (F) and urinary sodium excretion (G) in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, #P < 0.05 vs basal Se-deficiency, n=5/group). (H) The activity of GSH-Px in RPT cells with selenium-free incubation for 24 or 48 hours (*P < 0.05 vs the time 0, n=5/group). (I, J) The mRNA (I) and protein expression (J) of AT1R in selenium-free incubated RPT cells (Se-) and selenium-replete cells (Se+) for 48 hours. AT1R mRNA and protein levels were normalized using GAPDH (*P < 0.05 vs Se+, n=4–5/group). (K) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells from normotensive WKY rats. Cells were incubated with selenium-free media for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal, n=5; #P < 0.05 vs Ang II in Se+ group, n=5/group). (L) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells from Agtr1−/ mice. Cells were incubated with selenium-free media for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs control; #P < 0.05 vs Ang II in Se+ group, n=6/group).
Fig. 3.
Fig. 3.. Role of GPxl in the increased renal AT1R expression in selenium-deficient rats.
(A, B) Heatmap (A) and volcano plot (B) of 24 selenoproteins mRNA expression in the renal cortex of SD rats fed the selenium-deficient diet for 16 weeks. (C) The protein expression of GPx1 in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n=5/group). SeN, Se-normal; SeD, Se-deficiency. (D, E) The mRNA (D) and protein expression (E) of GPx1 in WKY RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=4–5/group). Se-, selenium-deficient cells; Se+, selenium-replete cells. (F) The levels of hydrogen peroxide (H2O2) in selenium-replete RPT cells treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control, n=5/group). (G, H) The mRNA (G) and protein expression (H) of AT1R in selenium-replete RPT cells treated with GPx1 siRNA (S) for 48 hours (*P < 0.05 vs control (C), n=4–5/group). (I) Effect of Ang II on Na+-K+-ATPase activity in RPT cells treated with GPx1 siRNA. RPT cells were incubated with GPx1 siRNA for 48 hours, and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal; #P < 0.05 vs Ang II in control group, n=5/group). (J, K) The mRNA (J) and protein expression (K) of AT1R in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours. AT1R mRNA and protein levels were normalized using GAPDH (*P < 0.05 vs Se+, n=4–5/group). (L) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells treated with ebselen. Cells were incubated with selenium-free media and ebselen (30 μm) for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal, n=5; #P < 0.05 vs Ang II in Se+ group, n=5/group).
Fig. 3.
Fig. 3.. Role of GPxl in the increased renal AT1R expression in selenium-deficient rats.
(A, B) Heatmap (A) and volcano plot (B) of 24 selenoproteins mRNA expression in the renal cortex of SD rats fed the selenium-deficient diet for 16 weeks. (C) The protein expression of GPx1 in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n=5/group). SeN, Se-normal; SeD, Se-deficiency. (D, E) The mRNA (D) and protein expression (E) of GPx1 in WKY RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=4–5/group). Se-, selenium-deficient cells; Se+, selenium-replete cells. (F) The levels of hydrogen peroxide (H2O2) in selenium-replete RPT cells treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control, n=5/group). (G, H) The mRNA (G) and protein expression (H) of AT1R in selenium-replete RPT cells treated with GPx1 siRNA (S) for 48 hours (*P < 0.05 vs control (C), n=4–5/group). (I) Effect of Ang II on Na+-K+-ATPase activity in RPT cells treated with GPx1 siRNA. RPT cells were incubated with GPx1 siRNA for 48 hours, and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal; #P < 0.05 vs Ang II in control group, n=5/group). (J, K) The mRNA (J) and protein expression (K) of AT1R in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours. AT1R mRNA and protein levels were normalized using GAPDH (*P < 0.05 vs Se+, n=4–5/group). (L) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells treated with ebselen. Cells were incubated with selenium-free media and ebselen (30 μm) for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal, n=5; #P < 0.05 vs Ang II in Se+ group, n=5/group).
Fig. 3.
Fig. 3.. Role of GPxl in the increased renal AT1R expression in selenium-deficient rats.
(A, B) Heatmap (A) and volcano plot (B) of 24 selenoproteins mRNA expression in the renal cortex of SD rats fed the selenium-deficient diet for 16 weeks. (C) The protein expression of GPx1 in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n=5/group). SeN, Se-normal; SeD, Se-deficiency. (D, E) The mRNA (D) and protein expression (E) of GPx1 in WKY RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=4–5/group). Se-, selenium-deficient cells; Se+, selenium-replete cells. (F) The levels of hydrogen peroxide (H2O2) in selenium-replete RPT cells treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control, n=5/group). (G, H) The mRNA (G) and protein expression (H) of AT1R in selenium-replete RPT cells treated with GPx1 siRNA (S) for 48 hours (*P < 0.05 vs control (C), n=4–5/group). (I) Effect of Ang II on Na+-K+-ATPase activity in RPT cells treated with GPx1 siRNA. RPT cells were incubated with GPx1 siRNA for 48 hours, and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal; #P < 0.05 vs Ang II in control group, n=5/group). (J, K) The mRNA (J) and protein expression (K) of AT1R in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours. AT1R mRNA and protein levels were normalized using GAPDH (*P < 0.05 vs Se+, n=4–5/group). (L) Effect of Ang II on Na+-K+-ATPase activity in selenium-deficient RPT cells treated with ebselen. Cells were incubated with selenium-free media and ebselen (30 μm) for 48 hours and then treated with Ang II (10−11 M) for 30 minutes (*P < 0.05 vs basal, n=5; #P < 0.05 vs Ang II in Se+ group, n=5/group).
Fig. 4.
Fig. 4.. Increased oxidative stress in selenium-deficient rats.
(A) Serum MDA levels in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (B, C) Fluorescence microscopy images (B) and quantification (C) of renal ROS production in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (D) The levels of renal hydrogen peroxide in the kidney of SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (E) The activity of renal GSH-Px in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (F, G) Fluorescence microscopy images (F) and quantification (G) of ROS production in WKY RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=5 /group). (H) The levels of hydrogen peroxide in RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=5/group). (I) The levels of hydrogen peroxide in RPT cells incubated with selenium-free media and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+, n=5/group).
Fig. 4.
Fig. 4.. Increased oxidative stress in selenium-deficient rats.
(A) Serum MDA levels in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (B, C) Fluorescence microscopy images (B) and quantification (C) of renal ROS production in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (D) The levels of renal hydrogen peroxide in the kidney of SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (E) The activity of renal GSH-Px in SD rats fed the selenium-deficient diet for 16 weeks (*P < 0.05 vs Se-normal, n=5/group). (F, G) Fluorescence microscopy images (F) and quantification (G) of ROS production in WKY RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=5 /group). (H) The levels of hydrogen peroxide in RPT cells incubated with selenium-free media for 48 hours (*P < 0.05 vs Se+, n=5/group). (I) The levels of hydrogen peroxide in RPT cells incubated with selenium-free media and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+, n=5/group).
Fig. 5.
Fig. 5.. Effects of tempol in the regulation of blood pressure and sodium excretion in selenium-deficient rats.
After feeding the indicated diet for 12 weeks, selenium-deficient rats or selenium-normal rats were then treated with tempol (1 mM) for 4 weeks. (A, B) Systolic- (SBP, A) and diastolic blood pressures (DBP, B) in selenium-deficient rats treated with tempol (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (C, D) 24-hours urine volume (C) and urine sodium excretion (UNa, D) in selenium-deficient rats treated with tempol (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (E, F) The mRNA (E) and protein expression (F) of AT1R in selenium-deficient rats treated with tempol (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol in the serum MDA levels in selenium-deficient rats (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group).
Fig. 5.
Fig. 5.. Effects of tempol in the regulation of blood pressure and sodium excretion in selenium-deficient rats.
After feeding the indicated diet for 12 weeks, selenium-deficient rats or selenium-normal rats were then treated with tempol (1 mM) for 4 weeks. (A, B) Systolic- (SBP, A) and diastolic blood pressures (DBP, B) in selenium-deficient rats treated with tempol (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (C, D) 24-hours urine volume (C) and urine sodium excretion (UNa, D) in selenium-deficient rats treated with tempol (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (E, F) The mRNA (E) and protein expression (F) of AT1R in selenium-deficient rats treated with tempol (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol in the serum MDA levels in selenium-deficient rats (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group).
Fig. 6.
Fig. 6.. Selenium-deficiency increased renal NF-κB activity by GPx1/ROS in selenium-deficient rats.
(A) The ratio of phosphorylated p65/total p65 expression in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). SeN, Se-normal; SeD, Se-deficiency. (B, C) The protein expression of NF-κB p65 in the cytoplasm (B) and nucleus (C) from the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). (D) Effect of selenium deficiency on the binding of NF-κB at the AT1R gene promoter in the renal cortex of SD rats. The binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from the renal cortex of selenium-normal (lane 4) and selenium-deficient (lane 5) rats by EMSA. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (E, F) The cytoplasmic- (E) and nuclear (F) protein expression of NF-κB p65 in selenium-deficient rats treated with tempol (1 mM) for 4 weeks (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol on the binding of NF-κB at the AT1R gene promoter in the renal cortex of selenium-deficient rats. After treatment with tempol (1 mM) for 4 weeks, the binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from kidney of selenium-normal and selenium-deficient rats by EMSA. Lane 4, selenium-normal rats; lane 5: selenium-normal rats treated with tempol; lane 6, selenium-deficient rats; lane 7, selenium-deficient rats treated with tempol. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (H, I) The mRNA (H) and protein expression (I) of AT1R in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (J, K) The cytoplasmic- (J) and nuclear (K) protein expression of NF-κB p65 in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3/group). (L, M) The mRNA (L) and protein expression (M) of AT1R in selenium-deficient RPT cells incubated with PDTC (10 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (N, O) The cytoplasmic- (N) and nuclear (O) protein expression of NF-κB p65 in selenium-replete RPT cells treated with GPx1 siRNA (Si) for 48 hours (*P < 0.05 vs control (C), n=5/group). (P, Q) The mRNA (P) and protein expression (Q) of AT1R in selenium-replete RPT cells incubated with PDTC (10 μM) for 30 minutes, and then treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control; #P < 0.05 vs siGPx1, n=3–4/group). (R, S) The cytoplasmic- (R) and nuclear (S) protein expression of NF-κB p65 in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=5/group).
Fig. 6.
Fig. 6.. Selenium-deficiency increased renal NF-κB activity by GPx1/ROS in selenium-deficient rats.
(A) The ratio of phosphorylated p65/total p65 expression in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). SeN, Se-normal; SeD, Se-deficiency. (B, C) The protein expression of NF-κB p65 in the cytoplasm (B) and nucleus (C) from the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). (D) Effect of selenium deficiency on the binding of NF-κB at the AT1R gene promoter in the renal cortex of SD rats. The binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from the renal cortex of selenium-normal (lane 4) and selenium-deficient (lane 5) rats by EMSA. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (E, F) The cytoplasmic- (E) and nuclear (F) protein expression of NF-κB p65 in selenium-deficient rats treated with tempol (1 mM) for 4 weeks (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol on the binding of NF-κB at the AT1R gene promoter in the renal cortex of selenium-deficient rats. After treatment with tempol (1 mM) for 4 weeks, the binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from kidney of selenium-normal and selenium-deficient rats by EMSA. Lane 4, selenium-normal rats; lane 5: selenium-normal rats treated with tempol; lane 6, selenium-deficient rats; lane 7, selenium-deficient rats treated with tempol. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (H, I) The mRNA (H) and protein expression (I) of AT1R in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (J, K) The cytoplasmic- (J) and nuclear (K) protein expression of NF-κB p65 in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3/group). (L, M) The mRNA (L) and protein expression (M) of AT1R in selenium-deficient RPT cells incubated with PDTC (10 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (N, O) The cytoplasmic- (N) and nuclear (O) protein expression of NF-κB p65 in selenium-replete RPT cells treated with GPx1 siRNA (Si) for 48 hours (*P < 0.05 vs control (C), n=5/group). (P, Q) The mRNA (P) and protein expression (Q) of AT1R in selenium-replete RPT cells incubated with PDTC (10 μM) for 30 minutes, and then treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control; #P < 0.05 vs siGPx1, n=3–4/group). (R, S) The cytoplasmic- (R) and nuclear (S) protein expression of NF-κB p65 in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=5/group).
Fig. 6.
Fig. 6.. Selenium-deficiency increased renal NF-κB activity by GPx1/ROS in selenium-deficient rats.
(A) The ratio of phosphorylated p65/total p65 expression in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). SeN, Se-normal; SeD, Se-deficiency. (B, C) The protein expression of NF-κB p65 in the cytoplasm (B) and nucleus (C) from the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). (D) Effect of selenium deficiency on the binding of NF-κB at the AT1R gene promoter in the renal cortex of SD rats. The binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from the renal cortex of selenium-normal (lane 4) and selenium-deficient (lane 5) rats by EMSA. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (E, F) The cytoplasmic- (E) and nuclear (F) protein expression of NF-κB p65 in selenium-deficient rats treated with tempol (1 mM) for 4 weeks (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol on the binding of NF-κB at the AT1R gene promoter in the renal cortex of selenium-deficient rats. After treatment with tempol (1 mM) for 4 weeks, the binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from kidney of selenium-normal and selenium-deficient rats by EMSA. Lane 4, selenium-normal rats; lane 5: selenium-normal rats treated with tempol; lane 6, selenium-deficient rats; lane 7, selenium-deficient rats treated with tempol. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (H, I) The mRNA (H) and protein expression (I) of AT1R in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (J, K) The cytoplasmic- (J) and nuclear (K) protein expression of NF-κB p65 in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3/group). (L, M) The mRNA (L) and protein expression (M) of AT1R in selenium-deficient RPT cells incubated with PDTC (10 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (N, O) The cytoplasmic- (N) and nuclear (O) protein expression of NF-κB p65 in selenium-replete RPT cells treated with GPx1 siRNA (Si) for 48 hours (*P < 0.05 vs control (C), n=5/group). (P, Q) The mRNA (P) and protein expression (Q) of AT1R in selenium-replete RPT cells incubated with PDTC (10 μM) for 30 minutes, and then treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control; #P < 0.05 vs siGPx1, n=3–4/group). (R, S) The cytoplasmic- (R) and nuclear (S) protein expression of NF-κB p65 in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=5/group).
Fig. 6.
Fig. 6.. Selenium-deficiency increased renal NF-κB activity by GPx1/ROS in selenium-deficient rats.
(A) The ratio of phosphorylated p65/total p65 expression in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). SeN, Se-normal; SeD, Se-deficiency. (B, C) The protein expression of NF-κB p65 in the cytoplasm (B) and nucleus (C) from the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). (D) Effect of selenium deficiency on the binding of NF-κB at the AT1R gene promoter in the renal cortex of SD rats. The binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from the renal cortex of selenium-normal (lane 4) and selenium-deficient (lane 5) rats by EMSA. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (E, F) The cytoplasmic- (E) and nuclear (F) protein expression of NF-κB p65 in selenium-deficient rats treated with tempol (1 mM) for 4 weeks (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol on the binding of NF-κB at the AT1R gene promoter in the renal cortex of selenium-deficient rats. After treatment with tempol (1 mM) for 4 weeks, the binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from kidney of selenium-normal and selenium-deficient rats by EMSA. Lane 4, selenium-normal rats; lane 5: selenium-normal rats treated with tempol; lane 6, selenium-deficient rats; lane 7, selenium-deficient rats treated with tempol. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (H, I) The mRNA (H) and protein expression (I) of AT1R in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (J, K) The cytoplasmic- (J) and nuclear (K) protein expression of NF-κB p65 in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3/group). (L, M) The mRNA (L) and protein expression (M) of AT1R in selenium-deficient RPT cells incubated with PDTC (10 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (N, O) The cytoplasmic- (N) and nuclear (O) protein expression of NF-κB p65 in selenium-replete RPT cells treated with GPx1 siRNA (Si) for 48 hours (*P < 0.05 vs control (C), n=5/group). (P, Q) The mRNA (P) and protein expression (Q) of AT1R in selenium-replete RPT cells incubated with PDTC (10 μM) for 30 minutes, and then treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control; #P < 0.05 vs siGPx1, n=3–4/group). (R, S) The cytoplasmic- (R) and nuclear (S) protein expression of NF-κB p65 in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=5/group).
Fig. 6.
Fig. 6.. Selenium-deficiency increased renal NF-κB activity by GPx1/ROS in selenium-deficient rats.
(A) The ratio of phosphorylated p65/total p65 expression in the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). SeN, Se-normal; SeD, Se-deficiency. (B, C) The protein expression of NF-κB p65 in the cytoplasm (B) and nucleus (C) from the renal cortex of selenium-deficient rats (*P < 0.05 vs Se-normal, n= 5/group). (D) Effect of selenium deficiency on the binding of NF-κB at the AT1R gene promoter in the renal cortex of SD rats. The binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from the renal cortex of selenium-normal (lane 4) and selenium-deficient (lane 5) rats by EMSA. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (E, F) The cytoplasmic- (E) and nuclear (F) protein expression of NF-κB p65 in selenium-deficient rats treated with tempol (1 mM) for 4 weeks (*P < 0.05 vs Se-normal; #P < 0.05 vs Se-deficiency, n=5/group). (G) Effect of tempol on the binding of NF-κB at the AT1R gene promoter in the renal cortex of selenium-deficient rats. After treatment with tempol (1 mM) for 4 weeks, the binding ability of the AT1R gene promoter, which contains a NF-κB site, was determined in nuclear protein from kidney of selenium-normal and selenium-deficient rats by EMSA. Lane 4, selenium-normal rats; lane 5: selenium-normal rats treated with tempol; lane 6, selenium-deficient rats; lane 7, selenium-deficient rats treated with tempol. No nuclear extracts (lane 1), 100 times of unlabeled probe (lane 2) or mutant probe (lane 3) were added to the reaction mixture as controls. (H, I) The mRNA (H) and protein expression (I) of AT1R in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (J, K) The cytoplasmic- (J) and nuclear (K) protein expression of NF-κB p65 in selenium-deficient RPT cells treated with tempol (100 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3/group). (L, M) The mRNA (L) and protein expression (M) of AT1R in selenium-deficient RPT cells incubated with PDTC (10 μM) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=3–4/group). (N, O) The cytoplasmic- (N) and nuclear (O) protein expression of NF-κB p65 in selenium-replete RPT cells treated with GPx1 siRNA (Si) for 48 hours (*P < 0.05 vs control (C), n=5/group). (P, Q) The mRNA (P) and protein expression (Q) of AT1R in selenium-replete RPT cells incubated with PDTC (10 μM) for 30 minutes, and then treated with GPx1 siRNA for 48 hours (*P < 0.05 vs control; #P < 0.05 vs siGPx1, n=3–4/group). (R, S) The cytoplasmic- (R) and nuclear (S) protein expression of NF-κB p65 in RPT cells with selenium-free incubation and a GPX1 mimic ebselen (Ebs) treatment (30 μm) for 48 hours (*P < 0.05 vs Se+; #P < 0.05 vs Se-, n=5/group).
Fig. 7.
Fig. 7.
Long-term selenium deficiency causes hypertension in SD rats, which is, at least in part, due to the decreased urine volume and sodium excretion. Selenium deficiency elevates H2O2 production, partially via reducing GPx1 expression, enhances NF-κB activity, aggravates AT1R expression and its-mediated renal function, causing urinary sodium retention and consequently increasing blood pressure.
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