SGK1 Polymorphisms

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The most recent issue of NephSAP (“Fluids, Electrolytes, and Acid-Base Disturbances”) features a mini-review describing the role of the kinase SGK1 in the regulation of various nephrology-related disorders, such as salt-sensitive hypertension, metabolic syndrome, and renal fibrosis. How does it work?

SGK1 stands for “serum and glucocorticoid-inducible kinase 1”, and it appears to regulate a number of key ion transport mechanisms within the nephron. Of particular relevance is the role of SGK1 in regulating sodium uptake in the collecting duct, where SGK1 enhances the activity of ENac by several mechanisms, including direct phosphorylation of the ENac channel while simultaneously inhibiting the kinase Nedd 4-2, which in the absence of SGK1 ubiquitinates and degrades ENac.

How does this relate to human disease? It turns out that there is a common polymorphism within the SGK1 gene, present in 2-3% of the Caucasian population and about 10% of the African-American population, which predisposes to the development of hypertension in the setting of hyperinsulinemia. Carriers of this polymorphism are also prone to develop an elevated BMI and thus this appears to be a key gene regulating metabolic syndrome. Perhaps drugs targeting SGK1 will be someday useful in the treatment of metabolic syndrome or regulating distal salt handling.

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