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1 Medicine, Georgetown University, Washington DC, District of Columbia, United States
2 Department of Medical Cell Biology, Uppsala University, Uppsala, Uppsala, Sweden
3 Medicine, Georgetown University, Washington DC, District of Columbia, United States; Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington DC, District of Columbia, United States
* To whom correspondence should be addressed. E-mail: ecelbarc{at}georgetown.edu.
Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, up-regulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected six-month-old male C57BL/CBA mice (n = 14/group) intraperitoneally (ip) with vehicle or 0.5 U/kg·bw insulin, and examined short-term (1-2 hour) sodium excretion and kidney ENaC-subunits (
-, 
-, and 
-), and serum and glucocorticoid-induced kinase (SGK-1), regulation. Insulin resulted in a significant reduction in urine sodium (by ~80%), that was restored by ip administration of the ENaC antagonist, benzamil (1.4 mg/kg·bw). Differential centrifugation followed by western-blotting of whole kidney revealed significantly increased band densities (by 26-85%) for insulin-, relative to vehicle-treated mice for - and -ENaC in the homogenate (H), and plasma-membrane-enriched fraction (MF), with no difference in the vesicle-enriched fraction (VF). Similarly -ENaC was significantly increased in MF (by 45%), but no change in the H. It was however, significantly decreased in the VF (by 28%) with insulin. In agreement, immunoperoxidase labeling demonstrated relatively stronger apical, relative to cytosolic, localization of -, - and -ENaC with insulin, whereas, with vehicle, labeling was fairly evenly dispersed throughout collecting duct principal cells. Furthermore, western-blotting showed insulin increased SGK-1 (by 75%) and phosphorylated-SGK band densities (by 30%) but only in the MF. These studies demonstrate novel, in vivo regulation of renal ENaC activity and subunit proteins and SGK-1 by insulin in the acute time frame in the mouse.
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