Oxidized low‐density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta

Chen, Liang; Wang, Qiushi; Xu, Yang; Niu, Na; Hu, Qingqing; Zhang, Baolong; Wu, Ming‐Ming; Yu, Changjiang; Chen, Xiao; Song, Bo; Zhang, Zhiren; Ma, Heping

doi:10.1111/bph.13853

Cited by 17 publications

(23 citation statements)

References 51 publications

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“…Our previous studies have shown that cholesterol elevates intracellular ROS in both lymphocytes and CCD principal cells (Liu, Song, et al, ; Song et al, ). We have also shown that hydrogen peroxide stimulates ENaC in cultured distal nephron cells (Ma, ) and that oxidized LDL significantly increased ENaC activity by elevating intracellular ROS (Liang et al, ). In this study, we show that increased intracellular cholesterol causes ROS probably by increasing 4‐HNE in ABCA1 KO mice.…”

Section: Discussionmentioning

confidence: 92%

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Chen

et al. 2019

British J Pharmacology

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Background and Purpose We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP‐binding cassette transporter A1; ABCA1). Experimental Approach We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell‐attached patch‐clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail‐cuff method. Key Results Specific deletion of ABCA1 elevated BP and ENaC single‐channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell‐expressed developmentally down‐regulated protein 4‐2 (Nedd4‐2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. Conclusions and Implications These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol‐dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4‐2, increased furin expression, and reduced cilium‐mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA‐induced hypertension.

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Section: Discussionmentioning

confidence: 92%

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Chen

et al. 2019

British J Pharmacology

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“…Not only aldosterone, but also Ox-LDL (oxidized low-density lipoprotein) has been found to stimulate ENaC activity in endothelial cells. This mechanism involves LOX-1 receptor (lectin-like ox-LDL receptor-1)-mediated activation of NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) and the inhibition of ENaC protects the endothelium from ox-LDL-induced dysfunction ( Liang et al, 2017 ). Interestingly, ENaCs are sensitive to stretch pressure and shear stress and responded to shear stress by increasing the Na (+) influx that could also contribute to endothelium dysfunction ( Guo et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The Deletion of Endothelial Sodium Channel α (αENaC) Impairs Endothelium-Dependent Vasodilation and Endothelial Barrier Integrity in Endotoxemia in Vivo

et al. 2018

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The role of epithelial sodium channel (ENaC) activity in the regulation of endothelial function is not clear. Here, we analyze the role of ENaC in the regulation of endothelium-dependent vasodilation and endothelial permeability in vivo in mice with conditional αENaC subunit gene inactivation in the endothelium (endo-αENaCKO mice) using unique MRI-based analysis of acetylcholine-, flow-mediated dilation and vascular permeability. Mice were challenged or not with lipopolysaccharide (LPS, from Salmonella typhosa, 10 mg/kg, i.p.). In addition, changes in vascular permeability in ex vivo organs were analyzed by Evans Blue assay, while changes in vascular permeability in perfused mesenteric artery were determined by a FITC-dextran-based assay. In basal conditions, Ach-induced response was completely lost, flow-induced vasodilation was inhibited approximately by half but endothelial permeability was not changed in endo-αENaCKO vs. control mice. In LPS-treated mice, both Ach- and flow-induced vasodilation was more severely impaired in endo-αENaCKO vs. control mice. There was also a dramatic increase in permeability in lungs, brain and isolated vessels as evidenced by in vivo and ex vivo analysis in endotoxemic endo-αENaCKO vs. control mice. The impaired endothelial function in endotoxemia in endo-αENaCKO was associated with a decrease of lectin and CD31 endothelial staining in the lung as compared with control mice. In conclusion, the activity of endothelial ENaC in vivo contributes to endothelial-dependent vasodilation in the physiological conditions and the preservation of endothelial barrier integrity in endotoxemia.

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“…However, the underlying mechanism remains unclear. We and other investigators have shown that ENaC is expressed in the endothelial cells and mediates vascular tension (Jeggle et al, 2013;Liang et al, 2018). Therefore, CsA may not only stimulate ENaC in the kidney but also activate ENaC in the endothelial cells, to increase blood pressure.…”

Section: Discussionmentioning

confidence: 91%

“…Since Cho-rich membrane microdomains are required for the assembly and activity of NADPH oxidase ( Vilhardt and van Deurs, 2004 ; Rao Malla et al, 2010 ), our data suggest that CsA-induced Cho accumulation in principal cells may account for activation of NADPH oxidase and the followed elevation of intracellular ROS. Our previous studies show that palmitate stimulates ENaC by increasing ROS in cultured distal nephron cells ( Wang et al, 2018 ) and that oxidized LDL also stimulates ENaC by increasing intracellular ROS ( Liang et al, 2018 ). In this study, we show that CsA increases ROS probably by increasing the expression of subunit of NADPH oxidase, p47 phox .…”

Section: Discussionmentioning

confidence: 99%

NaHS or Lovastatin Attenuates Cyclosporine A–Induced Hypertension in Rats by Inhibiting Epithelial Sodium Channels

et al. 2021

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The use of cyclosporine A (CsA) in transplant recipients is limited due to its side effects of causing severe hypertension. We have previously shown that CsA increases the activity of the epithelial sodium channel (ENaC) in cultured distal nephron cells. However, it remains unknown whether ENaC mediates CsA-induced hypertension and how we could prevent hypertension. Our data show that the open probability of ENaC in principal cells of split-open cortical collecting ducts was significantly increased after treatment of rats with CsA; the increase was attenuated by lovastatin. Moreover, CsA also elevated the levels of intracellular cholesterol (Cho), intracellular reactive oxygen species (ROS) via activation of NADPH oxidase p47phox, serum- and glucocorticoid-induced kinase isoform 1 (Sgk1), and phosphorylated neural precursor cell–expressed developmentally downregulated protein 4–2 (p-Nedd4-2) in the kidney cortex. Lovastatin also abolished CsA-induced elevation of α-, ß-, and γ-ENaC expressions. CsA elevated systolic blood pressure in rats; the elevation was completely reversed by lovastatin (an inhibitor of cholesterol synthesis), NaHS (a donor of H2S which ameliorated CsA-induced elevation of reactive oxygen species), or amiloride (a potent ENaC blocker). These results suggest that CsA elevates blood pressure by increasing ENaC activity via a signaling cascade associated with elevation of intracellular ROS, activation of Sgk1, and inactivation of Nedd4-2 in an intracellular cholesterol-dependent manner. Our data also show that NaHS ameliorates CsA-induced hypertension by inhibition of oxidative stress.

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Oxidized low‐density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 17 publications

References 51 publications

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

The Deletion of Endothelial Sodium Channel α (αENaC) Impairs Endothelium-Dependent Vasodilation and Endothelial Barrier Integrity in Endotoxemia in Vivo

NaHS or Lovastatin Attenuates Cyclosporine A–Induced Hypertension in Rats by Inhibiting Epithelial Sodium Channels

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