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Impaired aldosterone responsiveness in Corticosteroid Binding Globulin (CBG) deficient mice

Item Type:Article
Title:Impaired aldosterone responsiveness in Corticosteroid Binding Globulin (CBG) deficient mice
Creators Name:Sorensen, M.V. and Praetorius, H.A. and Nykjaer, A. and Willnow, T.E. and Leipziger, J.
Abstract:Aim: Corticosteroid Binding Globulin is the high affinity plasma carrier protein for cortisol. It keeps the steroids inactive, prevents them from degradation and defines the amount of free hormone acting on target tissues. Previous findings have shown insufficient responsiveness of corticosterone in peripheral tissues in CBG(-/-) mice despite elevated free plasma corticosterone. In the large intestine glucocorticoids synergistically enhance the pro-absorptive effects of aldosterone. We therefore hypothesized that CBG(-/-) mice have reduced responsiveness to aldosterone. Methods: We used CBG(-/-) and CBG(+/+) mice to investigate distal colonic electrogenic Na(+) absorption. An Ussing chamber was used to quantify amiloride-sensitive Na(+) transport in distal colonic mucosa (DeltaI(sc) (amil)) as a measure of the physiological effect of aldosterone. Results: No differences were observed in DeltaI(sc) (amil) or aldosterone levels in animals on control diet. When Na(+) restricted, CBG(+/+) mice responded with a marked up-regulation of DeltaI(sc) (amil) (25-fold). In CBG(-/-) mice this up-regulation was greatly attenuated as seen in a markedly reduced amiloride-sensitive short circuit current (reduced by approximately 50%), a reduced ability to lower faecal Na(+) excretion and a significantly attenuated up-regulation of the ENaC channel gamma-subunit. Diet-induced increases of total plasma aldosterone were similar in both genotypes but CBG(-/-) mice had an increased free plasma aldosterone fraction. Summary: This study defines the functional hyporesponsiveness and aldosterone resistance in distal colon of CBG(-/-) mice. This resistance occurs despite sufficient free corticosterone plasma level. Thus, steroid actions require an intrinsic but unknown function of CBG, which allows the sufficient supply of the hormone/s to the target tissue.
Keywords:Transcortin, ENaC, Distal Colon, Serpina6, Animals, Mice
Source:Acta Physiologica
ISSN:1748-1708
Publisher:Wiley-Blackwell (U.K.)
Volume:201
Number:1
Page Range:169-177
Date:January 2011
Official Publication:https://doi.org/10.1111/j.1748-1716.2010.02208.x
PubMed:View item in PubMed

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