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

Chang, Chiz-Tzung, Hung, Cheng-Chieh, Chen, Yung-Chang, Yen, Tzung-Hai, Wu, Mai-Szu, Yang, Chih-Wei, Phillips, Aled Owain ORCID: https://orcid.org/0000-0001-9744-7113 and Tian, Ya-Chung 2008. Transforming growth factor-β1 decreases epithelial sodium channel functionality in renal collecting duct cells via a Smad4-dependent pathway. Nephrology Dialysis Transplantation 23 (4) , pp. 1126-1134. 10.1093/ndt/gfm786

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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 α-ENaC promoter to assess the α-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 α-ENaC mRNA expression. The overexpression of Smad4 led to a decrease in AmsIsc, α-ENaC mRNA and α-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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine
Uncontrolled Keywords:	TGF-β1; Cortical collecting duct; Epithelial sodium channel; Short circuit current; Smad signalling pathway
Publisher:	Oxford University Press
ISSN:	0931-0509
Last Modified:	20 Oct 2022 08:16
URI:	https://orca.cardiff.ac.uk/id/eprint/27794

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