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NEW INVESTIGATOR AWARD IN REGULATORY AND INTEGRATIVE PHYSIOLOGY

Role of Sgk1 in salt and potassium homeostasis

¹Departments of Medicine and Pharmacology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California; ²Department of Clinical Neurobiology, University of Heidelberg; Departments of ³Pharmacology and ⁷Physiology I, University of Tübingen; ⁶Department of Biology, Chemistry and Pharmacy, Free University of Berlin, Germany; ⁴Department of Pharmacology, University of Lausanne, Switzerland; ⁵Department of Physiology, Innsbruck Medical University, Austria

Aldosterone plays a pivotal role in NaCl and K⁺ homeostasis by stimulation of Na⁺ reabsorption and K⁺ secretion in the aldosterone-sensitive distal nephron (ASDN). Recent studies demonstrated that the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by aldosterone in the ASDN and that polymorphisms of the kinase associate with arterial blood pressure in normotensive subjects. This review discusses the role of Sgk1 in NaCl and K⁺ homeostasis as evidenced by in vivo studies, including those in Sgk1-deficient mice. The studies indicate that Sgk1 is not absolutely required for Na⁺ reabsorption and K⁺ secretion in the ASDN. On a standard NaCl and K⁺ diet, modestly enhanced plasma aldosterone concentrations appear sufficient to establish a compensated phenotype in the absence of Sgk1. The kinase is necessary, however, for upregulation of transcellular Na⁺ reabsorption in the ASDN. This may involve Sgk1-mediated stimulation of basolateral Na⁺-K⁺-ATPase as well as retention of epithelial Na⁺ channel, ENaC, in the apical membrane. Such an upregulation is a prerequisite for adequate adaptation of 1) renal NaCl reabsorption during restricted dietary NaCl intake, as well as 2) K⁺ secretion in response to enhanced K⁺ intake. Thus gain-of-function mutations of Sgk1 are expected to result in renal NaCl retention and enhanced K⁺ secretion. Further studies are required to elucidate renal and nonrenal aldosterone-induced effects of Sgk1, the role of other Sgk1 activators, as well as the link of Sgk1 polymorphisms to arterial hypertension in humans.

sodium reabsorption; potassium excretion; aldosterone; protein kinases; kidney

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