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Trafficking of ENaC subunits in response to acute insulin in mouse kidney

¹Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington; ³Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, Washington, District of Columbia; and ²Department of Medical Cell Biology, Uppsala University, Biomedical Center, Uppsala, Sweden

Submitted 10 November 2006 ; accepted in final form 25 March 2007

Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, upregulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected 6-mo-old male C57BL/CBA mice (n = 14/group) intraperitoneally with vehicle or 0.5 U/kg body wt insulin and examined short-term (1–2 h) 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 intraperitoneal administration of the ENaC antagonist, benzamil (1.4 mg/kg body wt). Differential centrifugation followed by Western blotting of whole kidney revealed significantly increased band densities (by 26–103%) 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.

epithelial sodium channel; SGK-1; hyperinsulinemia

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