Local blockade of glucocorticoid activation reverses stress‐ and glucocorticoid‐induced delays in cutaneous wound healing

Youm, Jong-Kyung; Park, Kyungho; Uchida, Yoshikazu; Chan, Aegean; Mauro, Theodora M.; Holleran, Walter M.; Elias, Peter M.

doi:10.1111/wrr.12083

Cited by 31 publications

(36 citation statements)

References 41 publications

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“…Evidence of the deleterious effects of chronic GR overexpression and activation suggests that a selective GR antagonist would be a useful adjunct to the treatment of stress-related cognitive disorders (90, 236), as well as systemic problems as diverse as cardiometabolic syndromes (220) and wound healing (497), but to date there is none, in great measure due to the homologies of the LBDs of steroid receptors, as discussed above. RU-486, mifepristone, initially developed in search of a GR antagonist, is also a potent antagonist of the progesterone receptor.…”

Section: Mammalian Adrenocorticosteroids and Their Receptorsmentioning

confidence: 99%

“…Limited early trials with selective 11β-HSD1 antagonists improved glycemic control in obese type 2 diabetics (20, 219, 466). Selective 11β-HSD1 antagonists may also accelerate wound healing by decreasing GR-mediated effects that impede MR trophic and fibrotic repair effects (473, 497). Epigenetic events during gestation and early childhood related to growth restriction and/or stress increase the relative expression of 11β-HSD1:11β-HSD2 and are associated with cardiometabolic risk in the adult (81, 220, 375, 484).…”

Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 99%

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The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

277

224

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The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.

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Section: Mammalian Adrenocorticosteroids and Their Receptorsmentioning

confidence: 99%

Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 99%

The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

277

224

View full text Add to dashboard Cite

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“…11βHSD1 deficiency is also associated with enhanced angiogenesis in ischaemic tissues, resulting, for example, in improved left ventricular function following myocardial infarction in mice and potentially improving wound healing [97,98], a common problem in diabetes. Increased 11βHSD1 activity in ageing human fibroblasts leads to skin ageing and impaired wound healing, and topical application of an 11βHSD1 inhibitor improves wound healing in humans [99,100].…”

Section: Outstanding Challengesmentioning

confidence: 99%

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

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Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

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“…We previously reported that 11␤-HSD1 and H6PDH were expressed in the rat brain, including the whole hypothalamus (48); however, we did not study their colocalization within individual neurons essential for prereceptor modulation of a ligand and crucial global effects, even when expressed in a small number of neurons, as shown by Geerling et al (26). It has been postulated that the use of selective 11␤-HSD1 inhibitors would alleviate obesityand age-related maladies from cardiometabolic syndrome to dementia and problems with wound healing (55,59,110). However, the present findings suggest caution.…”

Section: Discussionmentioning

confidence: 88%

Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus

Chen

Gómez-Sánchez

Penman

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Activation of mineralocorticoid receptors (MR) of the hypothalamic paraventricular nucleus (PVN) increases sympathetic excitation. To determine whether MR and glucocorticoid receptors (GR) are expressed in preautonomic neurons of the PVN and how they relate to endogenous aldosterone levels in healthy rats, retrograde tracer was injected into the intermediolateral cell column at T4 to identify preautonomic neurons in the PVN. Expression of MR, GR, 11-␤ hydroxysteroid dehydrogenase1 and 2 (11␤-HSD1, 2), and hexose-6-phosphate dehydrogenase (H6PD) required for 11␤-HSD1 reductase activity was assessed by immunohistochemistry. RT-PCR and Western blot analysis were used to determine MR gene and protein expression. Most preautonomic neurons were in the caudal mediocellular region of PVN, and most expressed MR; none expressed GR. 11␤-HSD1, but not 11␤-HSD2 nor H6PD immunoreactivity, was detected in the PVN. In rats with chronic low or high sodium intakes, the low-sodium diet was associated with significantly higher plasma aldosterone, MR mRNA and protein expression, and c-Fos immunoreactivity within labeled preautonomic neurons. Plasma corticosterone and sodium and expression of tonicity-responsive enhancer binding protein in the PVN did not differ between groups, suggesting osmotic adaptation to the altered sodium intake. These results suggest that MR within preautonomic neurons in the PVN directly participate in the regulation of sympathetic nervous system drive, and aldosterone may be a relevant ligand for MR in preautonomic neurons of the PVN under physiological conditions. Dehydrogenase activity of 11␤-HSD1 occurs in the absence of H6PD, which regenerates NADP ϩ from NADPH and may increase MR gene expression under physiological conditions. mineralocorticoid receptor; aldosterone; sympathetic nervous system; preautonomic neuron; paraventricular nucleus; glucocorticoid receptor; 11-␤ hydroxysteroid dehydrogenase; sodium THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) and sympathetic nervous system (SNS) interact to maintain fluid, electrolyte, and hemodynamic homeostasis essential for terrestrial life where sodium intake is often limited. Both the RAAS and SNS are activated by a lowering sodium intake, adaptive mechanisms ensuring adequate blood pressure (17,51,52,60,64,104). The paraventricular nucleus (PVN), and the SNS were shown by ablation studies to have a crucial role in mineralocorticoid-salt excess models of hypertension (6, 58). Chronic systemic aldosterone excess, as well as the intracerebroventricular infusion of aldosterone administered at concentrations too low to be effective when infused systemically, increase blood pressure and SNS activity (35,61). In both models, the hypertension and sympathetic activation are prevented by the intracerebroventricular infusion of mineralocorticoid receptor (MR) antagonists at doses lower than the effective dose infused peripherally (35,39,61). Xue et al. (108) reproduced these pharmacological results with the intracerebroventricular infusion of MR siRNA (108).The ...

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Local blockade of glucocorticoid activation reverses stress‐ and glucocorticoid‐induced delays in cutaneous wound healing

Cited by 31 publications

References 41 publications

The Multifaceted Mineralocorticoid Receptor

The Multifaceted Mineralocorticoid Receptor

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus

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