Localization of Renal 1 β-Dehydrogenase by<i>in Situ</i>Hybridization: Autocrine not Paracrine Protector of the Mineralocorticoid Receptor

Stewart, Paul M.; Whorwood, C. B.; Barber, P. C.; Gregory, J.; Monder, Carl; Franklyn, Jayne A.; Sheppard, M. C.

doi:10.1210/endo-128-4-2129

Cited by 34 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3E),with exclusive labeling of CNT and principal cells, respectively. Less abundant labeling was also noted in distal convoluted tubule cells compared with CNT in the same rat (not shown), consistent with previous observations (3,8,27). In lithium-treated animals, there was distinctly less 11␤-HSD2 labeling in the cortical collecting duct (* in Fig.…”

Section: Corresponding Changes Between Mrna and Protein Expression Fosupporting

confidence: 90%

Altered expression of selected genes in kidney of rats with lithium-induced NDI

Rojek¹,

Nielsen²,

Brooks³

et al. 2005

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Lithium treatment is associated with development of nephrogenic diabetes insipidus, caused in part by downregulation of collecting duct aquaporin-2 (AQP2) and AQP3 expression. In the present study, we carried out cDNA microarray screening of gene expression in the inner medulla (IM) of lithium-treated and control rats, and selected genes were then investigated at the protein level by immunoblotting and/or immunohistochemistry. The following genes exhibited significantly altered transcription and mRNA expression levels, and these were compatible with the changes in protein expression. 11beta-Hydroxysteroid dehydrogenase type 2 protein expression in the IM was markedly increased (198 +/- 25% of controls, n = 6), and immunocytochemistry demonstrated an increased labeling of IM collecting duct (IMCD) principal cells. This indicated altered renal mineralocorticoid/glucocorticoid responses in lithium-treated rats. The inhibitor of cyclin-dependent kinases p27 (KIP) protein expression was significantly decreased or undetectable in the IMCD cells, pointing to increased cellular proliferation and remodeling. Heat shock protein 27 protein expression was decreased in the IM (64 +/- 6% of controls, n = 6), likely to be associated with the decreased medullary osmolality in lithium-treated rats. Consistent with this, lens aldose reductase protein expression was markedly decreased in the IM (16 +/- 2% of controls, n = 6), and immunocytochemistry revealed decreased expression in the thin limb cells in the middle and terminal parts of the IM. Ezrin protein expression was upregulated in the IM (158 +/- 16% of controls, n = 6), where it was predominantly expressed in the apical and cytoplasmic domain of the IMCD cells. Increased ezrin expression indicated remodeling of the actin cytoskeleton and/or altered regulation of IMCD transporters. In conclusion, the present study demonstrates changes in gene expression not only in the collecting duct but also in the thin limb of the loop of Henle in the IM, and several of these genes are linked to altered sodium and water reabsorption, cell cycling, and changes in interstitial osmolality.

show abstract

Section: Corresponding Changes Between Mrna and Protein Expression Fosupporting

confidence: 90%

Altered expression of selected genes in kidney of rats with lithium-induced NDI

Rojek¹,

Nielsen²,

Brooks³

et al. 2005

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…However, it has not been possible to demonstrate the existence of the truncated protein in vivo, and expression of the truncated cDNA in vitro produces a protein which, although immunoreactive with antisera to 'liver-type' lIP-HSD, is devoid of Ilp-HSD activity, in either dehydrogenase or reductase directions [64]. Indeed, it is likely that the discrepancy between the expression of 1 I@-HSD mRNA throughout the nephron [65,66] and the restriction of I Ip-HSD-like immunoreactivity to the proximal tubule reflects the expression of variant mRNA(s) in the distal nephron which are not translated [64].…”

Section: Problems With the 'One Enzyme' Hypothesis: A Second Paradoxmentioning

confidence: 99%

11β‐hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation

Seckl

1993

Eur J Clin Investigation

107

View full text Add to dashboard Cite

Abstract. 1 1 p-hydroxysteroid dehydrogenase (1 1 p-HSD) catalyzes the reversible conversion of physiological glucocorticoids (cortisol, corticosterone) to inactive products. The enzyme thus protects non-selective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone-selectivity in uivo), excludes maternal glucocorticoids from the foetal circulation and modulates glucocorticoid access to glucocorticoid receptors in other tissues. llP-HSD has been purified from rat liver, antisera raised, a cDNA isolated and its human homologue cloned. However, it is difficult to reconcile all of the actions of 1 1B-HSD with a single enzyme. Here data are reviewed that demonstrate not only molecular heterogeneity of the 'liver-type' 1 1P-HSD, but also the existence of a novel high affinity isoform in the placenta and perhaps distal nephron. These data are discussed in the light of their potential physiological and pathological importance, with particular reference to the pathogenesis of hypertension.

show abstract

“…Given that glucocorticoids are present at concentrations 10-100-fold higher than aldosterone, the specificity of the MR in epithelial tissues is conferred by the enzyme 11β-HSD2 (11β-hydroxysteroid dehydrogenase type 2) which converts glucocorticoids into their inactive metabolites (cortisone and 11-dehyroxycorticosterone) [28][29][30][31][32]. In non-epithelial tissues, such as neural and myocardial tissue, the MR is not co-localized with 11β-HSD2 and thus the MR in these tissues is normally occupied by glucocorticoids [10,11,33,34].…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

et al. 2013

View full text Add to dashboard Cite

MR (mineralocorticoid receptor) activation in the heart plays a central role in the development of cardiovascular disease, including heart failure. The MR is present in many cell types within the myocardium, including cardiomyocytes, macrophages and the coronary vasculature. The specific role of the MR in each of these cell types in the initiation and progression of cardiac pathophysiology is not fully understood. Cardiomyocyte MRs are increasingly recognized to play a role in regulating cardiac function, electrical conduction and fibrosis, through direct signal mediation and through paracrine MR-dependent activity. Although MR blockade in the heart is an attractive therapeutic option for the treatment of heart failure and other forms of heart disease, current antagonists are limited by side effects owing to MR inactivation in other tissues (including renal targets). This has led to increased efforts to develop therapeutics that are more selective for cardiac MRs and which may have reduced the occurrence of side effects in non-cardiac tissues. A major clinical consideration in the treatment of cardiovascular disease is of the differences between males and females in the incidence and outcomes of cardiac events. There is clinical evidence that female sensitivity to endogenous MRs is more pronounced, and experimentally that MR-targeted interventions may be more efficacious in females. Given that sex differences have been described in MR signalling in a range of experimental settings and that the MR and oestrogen receptor pathways share some common signalling intermediates, it is becoming increasingly apparent that the mechanisms of MRs need to be evaluated in a sex-selective manner. Further research targeted to identify sex differences in cardiomyocyte MR activation and signalling processes has the potential to provide the basis for the development of cardiac-specific MR therapies that may also be sex-specific.

show abstract

Localization of Renal 1 β-Dehydrogenase byin SituHybridization: Autocrine not Paracrine Protector of the Mineralocorticoid Receptor

Cited by 34 publications

References 0 publications

Altered expression of selected genes in kidney of rats with lithium-induced NDI

Altered expression of selected genes in kidney of rats with lithium-induced NDI

11β‐hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

Contact Info

Product

Resources

About