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Impaired aldosterone responsiveness in corticosteroid binding globulin deficient mice
Author(s) -
Sorensen M. V.,
Praetorius H. A.,
Nykjaer A.,
Willnow T.,
Leipziger J.
Publication year - 2011
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2010.02208.x
Subject(s) - aldosterone , medicine , endocrinology , corticosterone , transcortin , mineralocorticoid , amiloride , chemistry , ussing chamber , globulin , hormone , biology , secretion , sodium , organic chemistry
Aim: Corticosteroid binding globulin (CBG) 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 (ΔI sc (amil)) as a measure of the physiological effect of aldosterone. Results: No differences were observed in ΔI sc (amil) or aldosterone levels in animals on control diet. When Na + restricted, CBG +/+ mice responded with a marked up‐regulation of ΔI 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 ∼50%), a reduced ability to lower faecal Na + excretion and a significantly attenuated up‐regulation of the ENaC channel γ‐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.