Aberrant ENaC activation in Dahl salt-sensitive rats

Kakizoe, Yutaka; Kitamura, Kenichiro; Ko, Takehiro; Wakida, Naoki; Maekawa, Ai; Miyoshi, Takuji; Shiraishi, Naoki; Adachi, Masataka; Zhang, Zheng; Masilamani, Shyama; Tomita, Kimio

doi:10.1097/hjh.0b013e32832c7d23

Cited by 72 publications

(80 citation statements)

References 45 publications

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“…It was proposed that the expression of ENaC is abnormally regulated by dietary sodium in SS rats, and this abnormal expression is one of the factors causing salt-sensitive hypertension. [21][22][23][24] Here we confirm that ENaC expression is upregulated on a highsalt (HS) diet and provide direct evidence that ENaC activity is abnormally upregulated by dietary sodium in hypertensive SS rats, and this enhanced activity is one of the major factors causing salt-sensitive hypertension. In addition, our studies identify EGF as a key molecular substrate for a mechanism that diminishes development of salt-sensitive hypertension.…”

supporting

confidence: 63%

“…The authors demonstrated that a HS diet drives abnormal regulation of ENaC and SGK1 expression in SS rats in contrast with salt-resistant animals. 21,24,44 In addition to these previously published data, we have shown HS-induced ENaC activation in SS rats as directly measured by electrophysiology. Moreover, a unique chronic servocontrol technique was used here to uncover the role of high BP in driving ENaC expression in SS rats.…”

Section: Discussionmentioning

confidence: 80%

“…7 Benzamil, an ENaC inhibitor, 25 administered through the drinking water (15 mg/L), significantly reduced the level of salt-induced hypertension as previously observed with another ENaC inhibitor amiloride. 24 Protein expression profiles of b-and g-ENaC subunits were significantly increased in the kidney cortex of SS rats fed a HS diet compared with a LS diet (Figure 2, A and B). a-ENaC expression was not different in SS rats on a HS diet.…”

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 99%

“…Similar unchanged a-ENaC level and upregulation of b-and g-ENaC subunit expression and abundance (along with cleavage and shift of g-ENaC from 85 to 70 kD) was described in SS rats fed an 8% diet for 4 weeks. 24 Interestingly, an increase in a-ENaC, but not b-and g-ENaC, protein abundance was a result of aldosterone infusion in normal rats. 26 Although plasma aldosterone concentration is typically suppressed in SS rats on a HS diet, the activity of the intrarenal renin-angiotensin-aldosterone system is increased 27 and may contribute to the higher expression of b-and g-ENaC subunits.…”

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 99%

“…Although several studies suggest that ENaC expression is upregulated in SS rats, 21,24,34 the activity of the channel in any model of salt-sensitive hypertension has never been measured. To directly quantify the changes in ENaC activity in SS rats, collecting ducts were isolated and manually split open to access the apical plasma membrane.…”

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 99%

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Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na + absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na + transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a lowsalt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na + reabsorption in the collecting duct and the development of hypertension. More than 76 million American adults have high BP 1 and the likelihood of developing hypertension significantly increases with age. Nearly 40% of African Americans aged .20 years exhibit hypertension and nearly 70% of these individuals have a form of hypertension that is highly sensitive to salt intake. A reduced ability to maintain sodium homeostasis and normal levels of arterial pressure is a hallmark of all forms of hypertension. 2 In the kidney, discretionary Na + reabsorption in response to endocrine input to the aldosterone-sensitive distal nephron (ASDN) is a determinant of the pressurenatriuresis relationship, which is of fundamental importance in the long-term control of arterial pressure. 2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis. [5][6][7] The EGF and related hormones are multipotent agents [8][9][10][11] involved in regulation of various renal

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supporting

confidence: 63%

Section: Discussionmentioning

confidence: 80%

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 99%

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 99%

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 99%

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Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor

Mamenko

Zaika

Tomilin

et al. 2018

Journal Cellular Physiology

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ENaC-mediated sodium reabsorption in the collecting duct (CD) is a critical determinant of urinary sodium excretion. Existing evidence suggest direct stimulatory actions of Angiotensin II (Ang II) on ENaC in the CD, independently of the aldosterone-mineralocorticoid receptor (MR) signaling. Deletion of the major renal AT receptor isoform, AT R, decreases blood pressure and reduces ENaC abundance despite elevated aldosterone levels. The mechanism of this insufficient compensation is not known. Here, we used patch clamp electrophysiology in freshly isolated split-opened CDs to investigate how AT R dysfunction compromises functional ENaC activity and its regulation by dietary salt intake. Ang II had no effect on ENaC activity in CDs from AT R -/- mice suggesting no complementary contribution of AT receptors. We next found that AT R deficient mice had lower ENaC activity when fed with low (<0.01% Na ) and regular (0.32% Na ) but not with high (∼2% Na ) salt diet, when compared to the respective values obtained in Wild type (WT) animals. Inhibition of AT R with losartan in wild-type animals reproduces the effects of genetic ablation of AT R on ENaC activity arguing against contribution of developmental factors. Interestingly, manipulation with aldosterone-MR signaling via deoxycosterone acetate (DOCA) and spironolactone had much reduced influence on ENaC activity upon AT R deletion. Consistently, AT R -/- mice have a markedly diminished MR abundance in cytosol. Overall, we conclude that AT R deficiency elicits a complex inhibitory effect on ENaC activity by attenuating ENaC P and precluding adequate compensation via aldosterone cascade due to decreased MR availability.

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Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies

Du,

Li,

et al. 2024

Arch Toxicol

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Aberrant ENaC activation in Dahl salt-sensitive rats

Cited by 72 publications

References 45 publications

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor

Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies

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Aberrant ENaC activation in Dahl salt-sensitive rats

Cited by 72 publications

References 45 publications

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Compromised regulation of the collecting duct ENaC activity in mice lacking AT1a receptor

Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies

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Compromised regulation of the collecting duct ENaC activity in mice lacking AT_1a receptor