The overall goal of this research proposal is to understand the expression, regulation, and function of serum and glucocorticoid induced kinase 2 (sgk2) and the precise role it plays in sodium (Na+) transport across the nephron. The molecular basis underlying aldosterone-induced Na+ transport in the nephron has not been fully elucidated. Recently, sgk1 has been identified as a central mediator between early aldosterone effects and epithelial Na+ channel-mediated Na+ transport. Even more recently, two additional isoforms of sgk, sgk2 and sgk3, have been discovered. Localization of sgk2 expression and assessment of hormone-mediated sgk2 regulation will be performed through aldosterone and dexamethasone infusion in rats with subsequent sgk2 expression analyses by in situ hybridization and immunocytochemistry. Identification of downstream effectors of sgk2 will be performed through co-expression assays of Xenopus laevis oocytes with sgk2 and nephron segment-specific Na+ co-transporters. Finally, a tetracycline-inducible (Tet-On) sgk2 expression system in A6 cells will be constructed to isolate the specific effects of sgk2 on Na+ transport in a time-dependent manner. Given that inappropriate Na+ handling can result in extracellular fluid volume expansion and hypertension in humans, understanding the signaling pathways mediating aldosterone-induced Na+ transport in the kidney is clinically important.
| Pao, Alan C; Bhargava, Aditi; Di Sole, Francesca et al. (2010) Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney. Am J Physiol Renal Physiol 299:F1496-506 |
