Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

Kino, Tabito; Ishigami, Tomoaki; Murata, Tsumugi; Doi, Hiroshi; Nakashima-Sasaki, Rie; Chen, Lin; Sugiyama, Michiko; Azushima, Kengo; Wakui, Hiromichi; Minegishi, Shintaro; Tamura, Kouichi

doi:10.3390/ijms18061250

Cited by 8 publications

(5 citation statements)

References 40 publications

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“…64 Loss of Need4-2 in mice causes salt-sensitive hypertension and enhanced renal ENaC expression 65 resistant to eplerenone. 66 We observed that spironolactone markedly increased the ratio of total over phosphorylated form of Nedd4-2 in the kidney, indicative of higher protein activity and greater ENaC internalization in AngII-infused females, but not in males. This suggests lower ENaC activity due to higher protein degradation in spironolactone-treated females.…”

Section: Discussionmentioning

confidence: 64%

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: 64%

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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“…Body weight was measured twice a week. There is no literature showing the usage of sub dermic pellets of eplerenone in rodents, the choice of our dosage was similar than those chosen on previous studies where the eplerenone was added to chow (200 mg/kg pellet) (17,35,36). In our opinion the advantage of using pellets is that they deliver a constant and known dose of the drug Eplerenone to all animals regardless of the amount of food that each animal consumes.…”

Section: Animal Maintenance and Experimental Designmentioning

confidence: 99%

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division

et al. 2020

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Introduction: Mineralocorticoid receptor (MR) activation within adipose tissue, triggers inflammation and metabolic syndrome development. The pharmacological blockade of MR provides beneficial effects for adipose tissue. Our study evaluates the impact of eplerenone implantation upon obesity. Experimental approach: A group of mice with implanted placebo pellets were fed using two types of diet, a normal (ND) or a high fat (HFD) diet. Additionally, a group of mice fed HFD were implanted with an eplerenone pellet. Metabolic and biochemical parameters were assessed in each animal group. Adipocyte size and lipid accumulation were investigated in the liver and adipose tissue. We evaluated the components of renin-angiotensin-aldosterone system (RAAS) locally in adipose tissue. Key results: Eplerenone reduced HFD-induced body weight gain, fasting glucose levels, fat accumulation, HFD-induced adipocyte size and liver lipid accumulation and improved glucose tolerance. In the adipose tissue, HFD significantly increased the mRNA levels of the RAAS molecules relative to the ND group. Eplerenone lowered RAAS mRNA levels, components of lipid metabolism and markers of inflammation in HFD-fed animals. Conclusion: MR antagonism with eplerenone diminishes insulin resistance that is related to obesity partly via a reduction of RAAS activation, inflammatory progression and cytokines induction. This suggests that eplerenone should be further studied as a therapeutic option for obesity and overweight.

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“…Additionally, to determine detailed characteristics of salt-sensitive hypertension of the mice, we tried a mineral corticoid receptor antagonist treatment for Nedd4-2 C2 KO mice. Finally, us and other authors [63,64], have previously found that Nedd4-2 C2 KO mice showed eplerenone-resistant salt-sensitive hypertension [65] and enhanced electrophysiological abnormalities, after myocardial infarction [66], suggesting a pivotal role of the Nedd4-2 isoform with C2 domain for cardio-renal association, with regards to target-organ damages of the subjects with salt-sensitive hypertension.…”

Section: Generation Of Nedd4-2 C2 Ko Mice and Discovery Of Salt-sensitive Hypertension With Potential Contributions To Cardio-renal Involmentioning

confidence: 71%

“…Ultimately, we found that the lack of single isoform of the gene caused a significant change in vivo, resulting in a higher oral salt intake suppressing sodium excretion in urine and elevated blood pressures, the pathophysiology of which is called "salt-sensitive" [62]. In accordance with human genetic studies, the impairment of tubular sodium transport might be pivotal in the onset and development of salt-sensitive hypertension [65,66].…”

Section: Discussionmentioning

confidence: 84%

Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension

Ishigami

Kino

Minegishi

et al. 2020

IJMS

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Ubiquitination is a representative, reversible biological process of the post-translational modification of various proteins with multiple catalytic reaction sequences, including ubiquitin itself, in addition to E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, E3 ubiquitin ligase, deubiquitinating enzymes, and proteasome degradation. The ubiquitin–proteasome system is known to play a pivotal role in various molecular life phenomena, including the cell cycle, protein quality, and cell surface expressions of ion-transporters. As such, the failure of this system can lead to cancer, neurodegenerative diseases, cardiovascular diseases, and hypertension. This review article discusses Nedd4-2/NEDD4L, an E3-ubiquitin ligase involved in salt-sensitive hypertension, drawing from detailed genetic dissection analysis and the development of genetically engineered mice model. Based on our analyses, targeting therapeutic regulations of ubiquitination in the fields of cardio-vascular medicine might be a promising strategy in future. Although the clinical applications of this strategy are limited, compared to those of kinase systems, many compounds with a high pharmacological activity were identified at the basic research level. Therefore, future development could be expected.

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Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

Cited by 8 publications

References 40 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

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division

Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension

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