Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

Wu, Jing; Agbor, Larry N; Fang, Shi; Mukohda, Masashi; Nair, Anand; Nakagawa, Pablo; Sharma, Avika; Morgan, Donald A.; Grobe, Justin L; Rahmouni, Kamal; Weiß, Robert M.; McCormick, James A.; Sigmund, Curt D.

doi:10.1093/cvr/cvaa147

Cited by 20 publications

(29 citation statements)

References 46 publications

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“…A diet high in salt induced a modest increase in blood pressure in both wildtype and renin-b knockout mice. It was recently demonstrated that the C57BL6/J strain is salt-sensitive in response to overactivation of the sympathetic nervous system [30], but this remains controversial as there are other reports indicating that C57BL6/J are salt resistant [31,32]. Contrary to our prediction, renin-b lacking mice did not exhibit an augmented pressor response to salt.…”

Section: Discussioncontrasting

confidence: 99%

Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

Nakagawa

Gomez

et al. 2021

Preprint

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Excessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-b Null and wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-b Null and wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), was a trend for increased myocardial enlargement in Ren-b Null mice when compared with control mice. Multiple studies have also demonstrated the association of chronic and acute environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-b Null mice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies highlight a complex mechanism that masks/unmasks roles for renin-b in cardiovascular physiology.

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Section: Discussioncontrasting

confidence: 99%

Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

Nakagawa

Gomez

et al. 2021

Preprint

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“…but this remains controversial as there are other reports indicating that C57BL6/J are salt resistant [34,35]. Contrary to our prediction, renin-b lacking mice did not exhibit an augmented pressor response to salt.…”

Section: Plos Onecontrasting

confidence: 99%

Studies of salt and stress sensitivity on arterial pressure in renin-b deficient mice

Nakagawa

Gomez

et al. 2021

PLoS ONE

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Excessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNull and wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNull and wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), there was a trend for increased myocardial enlargement in Ren-bNull mice when compared with control mice, but this did not reach statistical significance. Multiple studies have also demonstrated the association of environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNull mice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies suggest that mechanisms unrelated to salt and acute stress alter the cardiovascular phenotype in mice lacking renin-b.

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“…Carotid artery and basilar artery, a cerebral resistance vessel, were studied because these vessels exhibit severe impairment of vasodilation capacity in response to genetic variations and excess salt intake. 6 , 24 …”

Section: Methodsmentioning

confidence: 99%

Endothelial Cullin3 Mutation Impairs Nitric Oxide-Mediated Vasodilation and Promotes Salt-Induced Hypertension

Fang

et al. 2022

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Human hypertension caused by in-frame deletion of CULLIN3 exon-9 (Cul3∆9) is driven by renal and vascular mechanisms. We bred conditionally activatable Cul3∆9 with tamoxifen-inducible Tie2-CREERT2 mice to test the importance of endothelial Cul3. The resultant mice (E-Cul3∆9) trended towards elevated nighttime blood pressure (BP) correlated with increased nighttime activity, but displayed no difference in daytime BP or activity. Male and female E-Cul3∆9 mice together exhibited a decline in endothelial-dependent relaxation in carotid artery. Male but not female E-Cul3∆9 mice displayed severe endothelial dysfunction in cerebral basilar artery. There was no impairment in mesenteric artery and no difference in smooth muscle function, suggesting the effects of Cul3∆9 are arterial bed-specific and sex-dependent. Expression of Cul3∆9 in primary mouse aortic endothelial cells decreased endogenous Cul3 protein, phosphorylated endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. Protein phosphatase (PP) 2A, a known Cul3 substrate, dephosphorylates eNOS. Cul3∆9-induced impairment of eNOS activity was rescued by a selective PP2A inhibitor okadaic acid, but not by a PP1 inhibitor tautomycetin. Because NO deficiency contributes to salt-induced hypertension, we tested the salt-sensitivity of E-Cul3∆9 mice. While both male and female E-Cul3∆9 mice developed salt-induced hypertension and renal injury, the pressor effect of salt was greater in female mutants. The increased salt-sensitivity in female E-Cul3∆9 mice was associated with decreased renovascular relaxation and impaired natriuresis in response to a sodium load. Thus, CUL3 mutations in the endothelium may contribute to human hypertension in part through decreased endothelial NO bioavailability, renovascular dysfunction, and increased salt-sensitivity of BP.

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Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

Cited by 20 publications

References 46 publications

Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

Studies of salt and stress sensitivity on arterial pressure in renin-b deficient mice

Endothelial Cullin3 Mutation Impairs Nitric Oxide-Mediated Vasodilation and Promotes Salt-Induced Hypertension

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