NDT Advance Access published online on November 8, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn614
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The role of Sgk-1 in the upregulation of transport proteins by PPAR-
agonists in human proximal tubule cells
Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
Correspondence and offprint requests to: Carol Pollock, Renal Research Laboratories, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia. Tel: +61-2-9926-7126; Fax: +61-2-9436-3719; E-mail: carpol{at}med.usyd.edu.au
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Abstract |
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Background. Cellular sodium and water transport are dysregulated in diabetes mellitus. Synthetic peroxisome proliferator-activated receptor gamma (PPAR-
) agonists are currently used in the treatment of type 2 diabetes, but their use is limited by fluid retention. Recent data suggest that PPAR- agonists stimulate distal tubular epithelial Na transport, potentially through the serine glucocorticoid kinase-1 (Sgk-1)-dependent regulation of the epithelial Na channel. We have recently demonstrated that Sgk-1 additionally regulates sodium reabsorption through the proximal tubular sodium hydrogen exchanger-3 (NHE3). However, the effects of PPAR- agonists on Sgk-1, the water channel proteins aquaporins and on sodium transport in human proximal tubule cells (PTCs) have not previously been studied.
Methods. PTCs were exposed to the PPAR- agonists, pioglitazone and the more selective PPAR- agonist L-805645 with and without the Sgk inhibitor (GSK650394A). PPAR-, Sgk-1, NHE3, AQP 1 and 7 mRNA and protein expression were determined by semi-quantitative PCR and western blot. The Sgk-1-specific effect was determined using Sgk-1 siRNA.
Results. Exposure of PTCs to 10 µM pioglitazone and 8 µM L-805645 increased the mRNA and protein expression of PPAR- (P < 0.005), NHE3 and Sgk-1 (both P < 0.05). The expression of AQPs 1 and 7 was increased by pioglitazone and L-805645 (both P < 0.05). The increases in NHE3 and AQPs 1 and 7 were significantly reduced by pharmacological inhibition of Sgk and when cultures were exposed to Sgk-1-specific siRNA.
Conclusions. PPAR- agonists enhanced the expression of NHE3, AQP 1 and 7 channels in human proximal tubule cells through Sgk-1-dependent pathways.
Keywords: diabetes mellitus; sodium transport; water channel
Received for publication: 2. 6.08
Accepted in revised form: 9.10.08
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