Conditional Deletion of
            <i>Hsd11b2</i>
            in the Brain Causes Salt Appetite and Hypertension

Evans, Louise; Ivy,; Wyrwoll, Caitlin; McNairn, Julie A.; Menzies, Robert; Christensen, Thorbjørn H.; Al-Dujaili, Emad A S; Kenyon, Christopher J.; Mullins, John J.; Seckl, Jonathan R.; Holmes, Megan C.; Bailey, Matthew A.

doi:10.1161/circulationaha.115.019341

Cited by 62 publications

(41 citation statements)

References 52 publications

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“…For example, deletion of the mineralocorticoid receptor in SMC in mice results in hypotension and protection from Ang II-induced pressor responses (24). Hypertension in apparent mineralocorticoid excess syndrome has been presumed to be caused by sodium retention in the distal nephron, but recent studies showed that deletion of the gene encoding 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) specifically in the brain caused increased salt sensitivity causing salt-sensitive hypertension independent of alterations in renal sodium excretion or fluid retention (25). The phenotype in S-CUL3Δ9 mice described herein demonstrates a plausible vascular mechanism contributing, at least in part, to severe early-onset hypertension seen in PHAII patients.…”

Section: Discussionmentioning

confidence: 99%

Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Agbor¹,

Ibeawuchi²,

Hu³

et al. 2016

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Agbor¹,

Ibeawuchi²,

Hu³

et al. 2016

JCI Insight

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“…Hsd11b2 in the murine brain triggers a central drive to consume salt (Evans et al, 2016). The rat Hsd2KO model offers a more robust platform to investigate the physiological mechanisms of central versus renal-centric salt sensitivity than is feasible in the mouse.…”

Section: Models Of Hypertensive Renal Damagementioning

confidence: 99%

Renal disease pathophysiology and treatment: contributions from the rat

Mullins

Conway

Menzies

et al. 2016

Disease Models &Amp; Mechanisms

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The rat has classically been the species of choice for pharmacological studies and disease modeling, providing a source of high-quality physiological data on cardiovascular and renal pathophysiology over many decades. Recent developments in genome engineering now allow us to capitalize on the wealth of knowledge acquired over the last century. Here, we review rat models of hypertension, diabetic nephropathy, and acute and chronic kidney disease. These models have made important contributions to our understanding of renal diseases and have revealed key genes, such as Ace and P2rx7, involved in renal pathogenic processes. By targeting these genes of interest, researchers are gaining a better understanding of the etiology of renal pathologies, with the promised potential of slowing disease progression or even reversing the damage caused. Some, but not all, of these target genes have proved to be of clinical relevance. However, it is now possible to generate more sophisticated and appropriate disease models in the rat, which can recapitulate key aspects of human renal pathology. These advances will ultimately be used to identify new treatments and therapeutic targets of much greater clinical relevance.

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“…Thus, reduced 11-HSD2 activity in the brain does not intrinsically cause hypertension, but it promotes salt hunger and salt sensitivity. The authors suggested that 11-HSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway [76]. …”

Section: Functional Roles Of 11-hsd2mentioning

confidence: 99%

Alterations of Cortisol Metabolism in Human Disorders

White

2018

Horm Res Paediatr

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The interconversion of active and inactive corticosteroids – cortisol and cortisone, respectively, in humans – is modulated by isozymes of 11β-hydroxysteroid dehydrogenase (11-HSD). Studies of this process have provided crucial insights into glucocorticoid effects in a wide variety of tissues. The 11-HSD1 isozyme functions mainly as an oxoreductase (cortisone to cortisol) and is expressed at high levels in the liver and other glucocorticoid target tissues. Because it is required for full physiological effects of cortisol, it has emerged as a drug target for metabolic syndrome and type 2 diabetes. Mutations in the corresponding HSD11B1 gene, or in the H6PD gene encoding hexose-6-phosphate dehydrogenase (which supplies the NADPH required for the oxoreductase activity of 11-HSD1), cause apparent cortisone reductase deficiency, a rare syndrome of adrenocortical hyperactivity and hyperandrogenism. In contrast, the 11-HSD2 isozyme functions as a dehydrogenase (cortisol to cortisone) and is expressed mainly in mineralocorticoid target tissues, where it bars access of cortisol to the mineralocorticoid receptor. Mutations in the HSD11B2 gene encoding 11-HSD2 cause the syndrome of apparent mineralocorticoid excess, a severe form of familial hypertension. The role of this enzyme in the pathogenesis of common forms of low-renin hypertension remains uncertain.

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Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension

Abstract: Supplemental Digital Content is available in the text.

Cited by 62 publications

References 52 publications

Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism

Renal disease pathophysiology and treatment: contributions from the rat

Alterations of Cortisol Metabolism in Human Disorders

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