Activation of autosomal recessive Pseudohypoaldosteronism1 ENaC with aldosterone

Shabbir, Waheed; Topcagic, Nermina; Aufy, Mohammed

doi:10.1016/j.ejphar.2021.174090

Cited by 8 publications

(8 citation statements)

References 28 publications

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“…This suggests lower ENaC activity due to higher protein degradation in spironolactone-treated females. In addition to increasing ENaC expression and abundance on the membrane, aldosterone was shown to stimulate the activity of the channel, 67–70 an effect that can be blocked by spironolactone. The exact mechanisms mediating aldosterone-induced increase in ENaC activity remain uncertain but may employ noncanonical signaling cascades involving membrane phospholipids, 71,72 methylation of the channel, 70,73 or generation of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Antagonism Is More Effective at Reducing Blood Pressure and Excessive Renal ENaC Activity in AngII-Infused Female Rats Than in Males

Buncha,

Cherezova,

Alexander

et al. 2023

Hypertension

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BACKGROUND: AngII (angiotensin II)-dependent hypertension causes comparable elevations of blood pressure (BP), aldosterone levels, and renal ENaC (epithelial Na + channel) activity in male and female rodents. Mineralocorticoid receptor (MR) antagonism has a limited antihypertensive effect associated with insufficient suppression of renal ENaC in male rodents with AngII-hypertension. While MR blockade effectively reduces BP in female mice with salt-sensitive and leptin-induced hypertension, MR antagonism has not been studied in female rodents with AngII-hypertension. We hypothesize that overstimulation of renal MR signaling drives redundant ENaC-mediated Na + reabsorption and BP increase in female rats with AngII-hypertension. METHODS: We employ a combination of physiological, pharmacological, biochemical, and biophysical approaches to compare the effect of MR inhibitors on BP and ENaC activity in AngII-infused male and female Sprague Dawley rats. RESULTS: MR blockade markedly attenuates AngII-hypertension in female rats but has only a marginal effect in males. Spironolactone increases urinary sodium excretion and urinary sodium-to-potassium ratio in AngII-infused female, but not male, rats. The expression of renal MR and HSD11β2 (11β-hydroxysteroid dehydrogenase type 2) that determines the availability of MR to aldosterone is significantly higher in AngII-infused female rats than in males. ENaC activity is ≈2× lower in spironolactone-treated AngII-infused female rats than in males. Reduced ENaC activity in AngII-infused female rats on spironolactone correlates with increased interaction with ubiquitin ligase Nedd4-2, targeting ENaC for degradation. CONCLUSIONS: MR-ENaC axis is the primary determinant of excessive renal sodium reabsorption and an attractive antihypertensive target in female rats with AngII-hypertension, but not in males.

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Section: Discussionmentioning

confidence: 99%

Aldosterone Antagonism Is More Effective at Reducing Blood Pressure and Excessive Renal ENaC Activity in AngII-Infused Female Rats Than in Males

Buncha,

Cherezova,

Alexander

et al. 2023

Hypertension

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“…PHA is a multisystemic disease caused by ENaC mutations, manifesting as sweat gland duct occlusion and eccrine glands inflammation due to salt accumulation developing into miliaria rubra, folliculitis, and atopic dermatitis-like skin lesions ( 122 ). The barrier function disruption of skin epithelium leads to increased Na + influx through ENaC, which activates fibroblasts via the COX-2/PGE2 pathway, resulting in fibrosis and the increased secretion of inflammatory cytokines.…”

Section: Role Of Epithelial Sodium Channel-related Inflammationmentioning

confidence: 99%

Role of epithelial sodium channel-related inflammation in human diseases

Chen

Zhang

et al. 2023

Front. Immunol.

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The epithelial sodium channel (ENaC) is a heterotrimer and is widely distributed throughout the kidneys, blood vessels, lungs, colons, and many other organs. The basic role of the ENaC is to mediate the entry of Na+ into cells; the ENaC also has an important regulatory function in blood pressure, airway surface liquid (ASL), and endothelial cell function. Aldosterone, serum/glucocorticoid kinase 1 (SGK1), shear stress, and posttranslational modifications can regulate the activity of the ENaC; some ion channels also interact with the ENaC. In recent years, it has been found that the ENaC can lead to immune cell activation, endothelial cell dysfunction, aggravated inflammation involved in high salt-induced hypertension, cystic fibrosis, pseudohypoaldosteronism (PHA), and tumors; some inflammatory cytokines have been reported to have a regulatory role on the ENaC. The ENaC hyperfunction mediates the increase of intracellular Na+, and the elevated exchange of Na+ with Ca2+ leads to an intracellular calcium overload, which is an important mechanism for ENaC-related inflammation. Some of the research on the ENaC is controversial or unclear; we therefore reviewed the progress of studies on the role of ENaC-related inflammation in human diseases and their mechanisms.

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“…Experiments were done as previously described. [43][44][45][46] Briefly, cells were grown in 100 µL cell culture dishes in 5% CO 2 incubator in DMEM medium supplemented with 5% fetal bovine serum. Medium was then aspirated, cells washed twice with PBS.…”

Section: Synthesis Route Amentioning

confidence: 99%

Design, Synthesis, and Lead Optimisation of CHVB Series Analogues as Potent Small Molecule Inhibitors of Chikungunya Virus

Battisti

Moesslacher

Abdelnabi

et al. 2022

Preprint

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The worldwide re-emerge of the Chikungunya virus (CHIKV), the high morbidity associated with it, and the lack of an available vaccine or antiviral treatment make the development of a potent CHIKV-inhibitor highly desirable. Therefore, an extensive lead optimisation was performed based on the previously reported CHVB compound 1b and the reported synthesis route was optimised - improving the overall yield in remarkable shorter synthesis and work-up time. 100 CHVB analogues were designed, synthesised, and investigated for their antiviral activity, physiochemistry, and toxicological profile. An extensive structure-activity relationship study (SAR) was performed, which focused mainly on the combination of scaffold changes and revealed the key chemical features for a high anti-CHIKV inhibition. Further, to investigate the druggability of the compound series, a thorough ADMET investigation was carried out: the compounds were screened for their aqueous solubility, lipophilicity, their toxicity in CaCo-2 cells, and possible hERG channel interactions. Additionally, 55 analogues were assessed for their metabolic stability in human liver microsomes (HLMs) which led to a structure-metabolism relationship study (SMR). The compounds showed an excellent safety profile, favourable physicochemical characteristics, and the required metabolic stability. A cross-resistance study confirmed the viral capping machinery (nsP1) to be the viral target of these second-generation CHVB compounds. This study identified five compounds (31b, 31d, 32d, 34, and 35d) as potent, safe, and stable lead compounds for further development as selective CHIKV inhibitors - with 32d as the most promising candidate. Finally, the collected insight led to a successful scaffold hop (64b) for future antiviral research studies.

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Activation of autosomal recessive Pseudohypoaldosteronism1 ENaC with aldosterone

Cited by 8 publications

References 28 publications

Aldosterone Antagonism Is More Effective at Reducing Blood Pressure and Excessive Renal ENaC Activity in AngII-Infused Female Rats Than in Males

Aldosterone Antagonism Is More Effective at Reducing Blood Pressure and Excessive Renal ENaC Activity in AngII-Infused Female Rats Than in Males

Role of epithelial sodium channel-related inflammation in human diseases

Design, Synthesis, and Lead Optimisation of CHVB Series Analogues as Potent Small Molecule Inhibitors of Chikungunya Virus

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