Sodium homeostasis is preserved in a global 11β‐hydroxysteroid dehydrogenase type 1 knockout mouse model

Christensen, Thorbjørn H.; Bailey, Matthew A.; Kenyon, Christopher J.; Jensen, Boye L.; Hunter, Robert W.

doi:10.1113/ep085177

Cited by 3 publications

(3 citation statements)

References 38 publications

(83 reference statements)

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“…Urine and feces were collected every 24 h and the sodium content of each was combined to provide daily sodium output. Flame photometry (BWB Technologies, United Kingdom) was used to measure sodium concentration in urine and the sodium content in dry feces following extraction in nitric acid (∼15 M; Thermo Fisher Scientific, United Kingdom), as described ( Christensen et al, 2015 ). Cumulative sodium balance (intake-output) was calculated over periods of 3 days.…”

Section: Methodsmentioning

confidence: 99%

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

et al. 2018

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Salt-sensitive hypertension is common in glucocorticoid excess. Glucocorticoid resistance also presents with hypercortisolemia and hypertension but the relationship between salt intake and blood pressure (BP) is not well defined. GRβgeo/+ mice have global glucocorticoid receptor (GR) haploinsufficiency and increased BP. Here we examined the effect of high salt diet on BP, salt excretion and renal blood flow in GRβgeo/+mice. Basal BP was ∼10 mmHg higher in male GRβgeo/+ mice than in GR+/+ littermates. This modest increase was amplified by ∼10 mmHg following a high-salt diet in GRβgeo/+ mice. High salt reduced urinary aldosterone excretion but increased renal mineralocorticoid receptor expression in both genotypes. Corticosterone, and to a lesser extent deoxycorticosterone, excretion was increased in GRβgeo/+ mice following a high-salt challenge, consistent with enhanced 24 h production. GR+/+ mice increased fractional sodium excretion and reduced renal vascular resistance during the high salt challenge, retaining neutral sodium balance. In contrast, sodium excretion and renal vascular resistance did not adapt to high salt in GRβgeo/+ mice, resulting in transient sodium retention and sustained hypertension. With high-salt diet, Slc12a3 and Scnn1a mRNAs were higher in GRβgeo/+ than controls, and this was reflected in an exaggerated natriuretic response to thiazide and benzamil, inhibitors of NCC and ENaC, respectively. Reduction in GR expression causes salt-sensitivity and an adaptive failure of the renal vasculature and tubule, most likely reflecting sustained mineralocorticoid receptor activation. This provides a mechanistic basis to understand the hypertension associated with loss-of-function polymorphisms in GR in the context of habitually high salt intake.

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Section: Methodsmentioning

confidence: 99%

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

et al. 2018

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“…Blood was collected by cardiac puncture immediately after cervical dislocation. Mouse and human activity radioimmunoassays were performed separately; mouse renin activity was determined as previously described ( 29 ), and human renin activity was determined using the Adaltis Renin radioimmunoassay kit (Ref. 12964, Adaltis, Italy).…”

Section: Methodsmentioning

confidence: 99%

Phenotypic dissection of the mouse Ren1d knockout by complementation with human renin

Nelson

Mullins

Sharp

et al. 2018

Journal of Biological Chemistry

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Normal renin synthesis and secretion is important for the maintenance of juxtaglomerular apparatus architecture. Mice lacking a functional Ren1d gene are devoid of renal juxtaglomerular cell granules and exhibit an altered macula densa morphology. Due to the species-specificity of renin activity, transgenic mice are ideal models for experimentally investigating and manipulating expression patterns of the human renin gene in a native cellular environment without confounding renin–angiotensin system interactions. A 55-kb transgene encompassing the human renin locus was crossed onto the mouse Ren1d-null background, restoring granulation in juxtaglomerular cells. Correct processing of human renin in dense core granules was confirmed by immunogold labeling. After stimulation of the renin–angiotensin system, juxtaglomerular cells contained rhomboid protogranules with paracrystalline contents, dilated rough endoplasmic reticulum, and electron-lucent granular structures. However, complementation of Ren1d−/− mice with human renin was unable to rescue the abnormality seen in macula densa structure. The juxtaglomerular apparatus was still able to respond to tubuloglomerular feedback in isolated perfused juxtaglomerular apparatus preparations, although minor differences in glomerular tuft contractility and macula densa cell calcium handling were observed. This study reveals that the human renin protein is able to complement the mouse Ren1d−/− non-granulated defect and suggests that granulopoiesis requires a structural motif that is conserved between the mouse Ren1d and human renin proteins. It also suggests that the altered macula densa phenotype is related to the activity of the renin-1d enzyme in a local juxtaglomerular renin–angiotensin system.

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“…It is plausible that 11βHSD1 regulates tubular sodium reabsorption by generating active glucocorticoid, since the stimulatory effects of moderate glucocorticoid excess are well-defined [ 53 ]. However, it is unlikely that the enzyme plays a major role in physiological salt balance, since 11βHSD1 knockout mice adapt perfectly well to dietary sodium restriction [ 54 ].…”

Section: βHsd1 and Hypertensionmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases and Hypertension in the Metabolic Syndrome

Bailey

2017

Curr Hypertens Rep

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The metabolic syndrome describes a clustering of risk factors—visceral obesity, dyslipidaemia, insulin resistance, and salt-sensitive hypertension—that increases mortality related to cardiovascular disease, type 2 diabetes, cancer, and non-alcoholic fatty liver disease. The prevalence of these concurrent comorbidities is ~ 25–30% worldwide, and metabolic syndrome therefore presents a significant global public health burden. Evidence from clinical and preclinical studies indicates that glucocorticoid excess is a key causal feature of metabolic syndrome. This is not increased systemic in circulating cortisol, rather increased bioavailability of active glucocorticoids within tissues. This review examines the role of covert glucocorticoid excess on the hypertension of the metabolic syndrome. Here, the role of the 11β-hydroxysteroid dehydrogenase enzymes, which exert intracrine and paracrine control over glucocorticoid signalling, is examined. 11βHSD1 amplifies glucocorticoid action in cells and contributes to hypertension through direct and indirect effects on the kidney and vasculature. The deactivation of glucocorticoid by 11βHSD2 controls ligand access to glucocorticoid and mineralocorticoid receptors: loss of function promotes salt retention and hypertension. As for hypertension in general, high blood pressure in the metabolic syndrome reflects a complex interaction between multiple systems. The clear association between high dietary salt, glucocorticoid production, and metabolic disorders has major relevance for human health and warrants systematic evaluation.

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Sodium homeostasis is preserved in a global 11β‐hydroxysteroid dehydrogenase type 1 knockout mouse model

Cited by 3 publications

References 38 publications

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

Phenotypic dissection of the mouse Ren1d knockout by complementation with human renin

11β-Hydroxysteroid Dehydrogenases and Hypertension in the Metabolic Syndrome

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