The Intrarenal Localization of Mineralocorticoid Receptors and 11β-Dehydrogenase: Immunocytochemical Studies

Rundle, Susan E.; Funder, John W.; Lakshmi, Vijaya M.; Monder, Carl

doi:10.1210/endo-125-3-1700

Cited by 107 publications

(29 citation statements)

References 18 publications

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“…Immunoreactive precipitates were consistently observed in both cytoplasm and nucleus of the epithelial cells of renal tubules and of those of several exocrine glands under various conditions in agreement with the reports of Krozowski et al (1989) and Rundle et al (1989). In the colonic columnar cells as well as renal tubular cells, the cytoplasmic localization of MR may reflect a non-genomic action of the receptor such as association with unknown factors proximally or distally involved in sodium transport.…”

Section: Discussionsupporting

confidence: 87%

Immunohistochemical Localization of Mineralocorticoid Receptor in Human Gut.

Fukushima

Sasano²,

Nishimura

et al. 1991

Tohoku J. Exp. Med.

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Section: Discussionsupporting

confidence: 87%

Immunohistochemical Localization of Mineralocorticoid Receptor in Human Gut.

Fukushima

Sasano²,

Nishimura

et al. 1991

Tohoku J. Exp. Med.

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“…The mRNA levels of 11␤-HSD1 and 11␤-HSD2, however, were found to be similar in SS rats and Dahl salt-resistant rats (15). 11␤-HSD1 is expressed in the kidney (2,35), but the functional significance of renal 11␤-HSD1 is virtually unknown.…”

Section: Discussionmentioning

confidence: 92%

“…One possibility is that excess glucocorticoids stimulate mineralocorticoid receptors, similar to that occurs with 11␤-HSD2 deficiencies. However, 11␤-HSD1 protein seems to be localized in proximal tubules and interstitial cells (2,35), rather than the distal nephron where mineralocorticoid receptors are expressed. A recent study indicated that hexose-6-phosphate dehydrogenase, which provides the NADPH needed for the reductase activity of 11␤-HSD1, was not readily detectable in renal inner medullary interstitial cells (19).…”

Section: Discussionmentioning

confidence: 96%

Renal medullary 11β-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension

Liu

Singh

Usa

et al. 2008

Physiological Genomics

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Liu Y, Singh RJ, Usa K, Netzel BC, Liang M. Renal medullary 11␤-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension. Physiol Genomics 36: 52-58, 2008. First published September 30, 2008 doi:10.1152/physiolgenomics.90283.2008.-The Dahl salt-sensitive rat is a widely used model of human salt-sensitive forms of hypertension. The kidney plays an important role in the pathogenesis of Dahl salt-sensitive hypertension, but the molecular mechanisms involved remain a subject of intensive investigation. Gene expression profiling studies suggested that 11␤-hydroxysteroid dehydrogenase type 1 might be dysregulated in the renal medulla of Dahl salt-sensitive rats. Additional analysis confirmed that renal medullary expression of 11␤-hydroxysteroid dehydrogenase type 1 was downregulated by a high-salt diet in SS-13 BN rats, a consomic rat strain with reduced blood pressure salt sensitivity, but not in Dahl salt-sensitive rats. 11␤-Hydroxysteroid dehydrogenase type 1 is known to convert inactive 11-dehydrocorticosterone to active corticosterone. The urinary corticosterone/11-dehydrocorticosterone ratio as well as urinary excretion of corticosterone was higher in Dahl salt-sensitive rats than in SS-13 BN rats. Knockdown of renal medullary 11␤-hydroxysteroid dehydrogenase type 1 with small-interfering RNA attenuated the early phase of salt-induced hypertension in Dahl salt-sensitive rats and reduced urinary excretion of corticosterone. Knockdown of 11␤-hydroxysteroid dehydrogenase type 1 did not affect blood pressure in SS-13 BN rats. Long-term attenuation of salt-induced hypertension was achieved with small hairpin RNA targeting renal medullary 11␤-hydroxysteroid dehydrogenase type 1. In summary, we have demonstrated that suppression of 11␤-hydroxysteroid dehydrogenase type 1 expression in the renal medulla attenuates salt-induced hypertension in Dahl salt-sensitive rats.

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“…11␤-HSD1 is also expressed in kidney, predominantly in the proximal tubule, interstitial cells, and medulla (601). Interestingly, HSD11B1 polymorphisms associate with blood pressure in some populations (172,201), and even with pressure changes to potassium challenge (266), although separating effects on blood pressure from metabolic syndrome as a whole is challenging and the low levels of 11␤-HSD1 mRNA in human kidney mitigate against a major role in this tissue.…”

Section: E Kidneymentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

736

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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The Intrarenal Localization of Mineralocorticoid Receptors and 11β-Dehydrogenase: Immunocytochemical Studies

Cited by 107 publications

References 18 publications

Immunohistochemical Localization of Mineralocorticoid Receptor in Human Gut.

Immunohistochemical Localization of Mineralocorticoid Receptor in Human Gut.

Renal medullary 11β-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

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