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NDT Advance Access originally published online on November 28, 2007
Nephrology Dialysis Transplantation 2008 23(4):1126-1134; doi:10.1093/ndt/gfm786
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Transforming growth factor-β1 decreases epithelial sodium channel functionality in renal collecting duct cells via a Smad4-dependent pathway

Chiz-Tzung Chang1,2, Cheng-Chieh Hung2, Yung-Chang Chen2, Tzung-Hai Yen3, Mai-Szu Wu2, Chih-Wei Yang2, Aled Phillips4 and Ya-Chung Tian2

1 Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan 2 Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 3 Histopathology Unit, London Research Institute, Cancer Research UK, London 4 Institute of Nephrology, Cardiff University, Wales, UK

Ya-Chung Tian, Department of Nephrology, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-shan 333, Taiwan. Tel: +886-3-3281200; Fax: +886-3-3282173; E-mail: dryctian{at}adm.cgmh.org.tw



  Abstract

Background. Transformation growth factor-β1 (TGF-β1) inhibits transepithelial sodium transport and suppresses the epithelial sodium channel (ENaC) in many different types of epithelial cells; however, the molecular mechanism of this effect in the kidney is still not clear. The aim of this study was to examine the regulation of transepithelial sodium transport by TGF-β1 in renal cells.

Methods. We derived stable mouse cortical collecting duct cell lines that overexpressed Smad4 or N-termianl truncated Smad4, and studied the effects of TGF-β1 on them. The equivalent electrical current (Ieq) was taken as representing transepithelial current and the amiloride sensitive short circuit current (AmsIsc) as representing the ENaC activity. We used real-time PCR to quantify the expression of ENaC and measurement of the luciferase activity of cells transiently transfected with a mouse {alpha}-ENaC promoter to assess the {alpha}-ENaC promoter activity.

Result. The administration of TGF-β1 decreased Ieq, mainly as a result of the decrease of AmsIsc, and it correlated with inhibition of the {alpha}-ENaC mRNA expression. The overexpression of Smad4 led to a decrease in AmsIsc, {alpha}-ENaC mRNA and {alpha}-ENaC promoter activity, but the overexpression of the N-terminal truncated Smad4 did not induce these changes. The TGF-β1-induced reduction of AmsIsc was alleviated in the N-terminal truncated Smad4-overexpressed cells.

Conclusion. It appears that the N-terminus region of Smad4 is indispensable in Smad4-mediated inhibition of the transepithelial sodium transport. TGF-β1 may decrease the ENaC functionality via a Smad4-dependent pathway.

Keywords: TGF-β1; cortical collecting duct; epithelial sodium channel; short circuit current; Smad signalling pathway

Received for publication: 31.10.06
Accepted in revised form: 8.10.07


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