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Serum- and glucocorticoid-inducible kinase (SGK) interacts with the chloride channel ClC-5 to regulate renal albumin uptake

D.H. Hryciw,1 J. Ekberg,1 A. Lee,1 N. Schimpf,1 S.-J. Conroy,1 C.C. Yun2 and P. Poronnik,1 1School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia and 2Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, USA.

The reuptake of albumin from the glomerular filtrate by the renal proximal tubule is a constitutive receptor-mediated endocytic process. This process requires a number of key membrane proteins including the scavenger receptor megalin, the Cl channel ClC-5 and the Na-H exchanger NHE3 that are thought to form the endocytic complex. In addition, albumin uptake is regulated by a number of accessory proteins including cofilin, Nedd4-2 and the PDZ (PSD95/Dlg/ZO-1) scaffold NHERF2. We have recently found that the serum- and glucocorticoid-inducible kinase SGK-1 regulates albumin uptake. Overexpression of SGK-1 significantly increased albumin uptake (114 ± 3.7%). In contrast, overexpression of ligase defective SGK-1 inhibited albumin uptake by 81 ± 3.1% (n=4, P < 0.05). SGK-1 has been previously reported to bind to NHERF2 via a PDZ binding motif. Therefore, we investigated if the effects of SGK-1 on albumin uptake were mediated by an interaction with the ClC-5-NHERF2 complex. An SGK-1 antibody was used to probe OK cell lysate and it was found that ClC-5 co-immunoprecipitated with SGK-1. However, when GST-pulldown experiments were performed using the C-terminus of ClC-5 (which binds NHERF2) there was no binding of SGK-1 detected. Interestingly, there are potential SGK-1 phosphorylation sites on the intracellular N-terminus of ClC-5 and we are currently investigating whether SGK-1 binds to this portion of the channel. Alternatively, SGK-1 may be exerting its effects via phosphorylation of as yet unidentified accessory proteins. These data suggest a novel role for SGK-1 in regulating albumin endocytosis via mechanisms that may not involve PDZ scaffold interactions.