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NDT Advance Access originally published online on January 31, 2008
Nephrology Dialysis Transplantation 2008 23(6):1834-1843; doi:10.1093/ndt/gfm923
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The role of SGK-1 in angiotensin II-mediated sodium reabsorption in human proximal tubular cells

Veronica A Stevens1, Sonia Saad1, Philip Poronnik2, Carol A Fenton-Lee1, Tania S Polhill1 and Carol A Pollock1

1 Department of Medicine, University of Sydney, Renal Research Group, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW 2065, Australia 2 School of Biomedical Sciences, Skerman Building 65, The University of Queensland, St Lucia, QLD 4072, Australia

Correspondence and offprint requests to: Correspondence and offprint requests to: C.A. Pollock, Department of Medicine, Level 3, Wallace Freeborn Building, Royal North Shore Hospital, Pacific Highway, St Leonards, NSW 2065, Australia. Tel: +61-2-9926-7126; Fax: +61-2-9436-3719; E-mail: carpol{at}med.usyd.edu.au



  Abstract

Background. The role of angiotensin II (Ang II) in mediating excessive sodium reabsorption in diabetic nephropathy is recognized. Serine-glucocorticoid kinase-1 (SGK-1) increases sodium–hydrogen exchanger-3 (NHE3) expression and is known to be upregulated in in vitro and in vivo models of diabetic nephropathy. However, a link between Ang II and SGK-1 in diabetic nephropathy has not been established.

Methods. Ang II production in cultured human proximal tubular cells was measured under normal (5 mM) and high (25 mM) glucose conditions. The Ang II type 1 receptor was identified by RT-PCR. SGK-1 and NHE3 mRNA and protein expression was measured in proximal tubule cells (PTCs) exposed to Ang II. EIPA inhibitable changes in cell sodium uptake were undertaken to confirm that alterations in NHE3 mRNA and protein were reflected in transport activity. SGK-1 was silenced in the PTCs using small interfering RNA to determine the role of SGK-1 in mediating Ang II-induced increases in NHE3-mediated sodium uptake.

Results. Ang II production by PTCs was significantly increased by exposure to high glucose (P < 0.02). Ang II increased NHE3 and SGK-1 mRNA expression to 275 ± 30% (P < 0.02) and 130 ± 10% (P < 0.05) respectively. Silencing of SGK-1 reduced Ang II-stimulated NHE3 protein expression to 49.8 ± 6.1% (P < 0.05) of control levels. SGK-1 silencing abolished increases in 22Na+ uptake seen in Ang II-treated cells to 86.7 ± 1.6% of control values.

Conclusion. These data suggest that increased sodium reabsorption in renal proximal tubular cells considered to be due to Ang II in diabetes mellitus is mediated through SGK-1 expression.

Keywords: angiotensin II; diabetes; human proximal tubule; Na+–H+ exchange; SGK-1

Received for publication: 5. 1.07
Accepted in revised form: 10.12.07


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