Impaired aldosterone responsiveness in corticosteroid binding globulin deficient mice

Area of Science:

• Endocrinology
• Physiology
• Molecular Biology

Background:

• Corticosteroid-binding globulin (CBG) is the primary carrier protein for cortisol, regulating hormone availability to target tissues.
• Glucocorticoids and aldosterone interact to regulate sodium absorption in the large intestine.
• CBG-deficient (CBG⁻(/)⁻) mice exhibit impaired peripheral tissue responsiveness to corticosterone.

Purpose of the Study:

• To investigate the role of CBG in aldosterone responsiveness in the distal colon.
• To determine if CBG deficiency leads to aldosterone resistance in the colonic epithelium.

Main Methods:

• Utilized CBG⁻(/)⁻ and wild-type (CBG(+/+)) mice.
• Employed Ussing chamber techniques to measure amiloride-sensitive sodium transport (ΔI(sc) (amil)) in distal colonic mucosa.
• Analyzed fecal sodium excretion and ENaC γ-subunit expression.

Main Results:

• CBG⁻(/)⁻ mice showed significantly attenuated upregulation of sodium absorption in response to sodium restriction compared to CBG(+/+) mice.
• Aldosterone resistance in CBG⁻(/)⁻ mice was characterized by reduced amiloride-sensitive short-circuit current and impaired fecal sodium excretion.
• Despite similar total plasma aldosterone levels, CBG⁻(/)⁻ mice had an increased free plasma aldosterone fraction, yet exhibited hyporesponsiveness.

Conclusions:

• CBG deficiency results in functional aldosterone resistance in the distal colon.
• This resistance occurs independently of free corticosterone levels, suggesting an intrinsic function of CBG.
• CBG plays a critical, yet unidentified, role in facilitating adequate steroid hormone supply to target tissues for proper physiological action.