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Blockade of the Effects of TGF-1 on Mesangial Cells by Overexpression of Smad7

Ruihua Chen^*, Cancan Huang, Thomas A. Morinelli^*, Maria Trojanowska^* and Richard V. Paul^*

*Departments of Medicine and Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina; and Medical Specialty Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina.

Correspondence to: Dr. Richard V. Paul, Division of Nephrology, Department of Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425. Phone: 803-792-4123; Fax: 803-792-8399; E-mail: paulr{at}musc.edu

ABSTRACT. Smad7, a protein induced by transforming growth factor–1 (TGF-1) in many target cells, inhibits TGF-1 signal transduction and is thought to mediate an intracellular negative feedback response that limits TGF-1 effects. It is possible that overexpression of Smad7 could block specified effects of TGF-1 on mesangial cells, a TGF- target in glomerular disease. Smad7 mRNA was induced by TGF-1 within 1 h in a concentration-dependent manner in a transformed mouse mesangial cell (MMC) line. Uptake of ¹⁴C-spermidine from the medium by MMC and the transcriptional activity of a segment of the human collagen pro-2 type 1 chain (COL1A2) promoter fused to a luciferase reporter gene were used as indices of TGF-1. Treatment with TGF-1 increased ¹⁴C-spermidine uptake rate in a time-, concentration-, and temperature-dependent manner. For example, exposure to 1 ng/ml TGF-1 for 15 h increased uptake approximately twofold, a response that was attenuated by cycloheximide. Transfection of Smad7 expression vector into MMC abrogated both TGF-1-dependent stimulation of spermidine uptake and COL1A2 promoter activity. It is concluded that: (1) TGF-1 induces Smad7 in MMC; (2) ¹⁴C-spermidine uptake is a convenient quantitative index of TGF-1 effect in these cells; and (3) overexpression of Smad7 is a highly effective method of blocking at least some mesangial cell effects of TGF-1 that may warrant evaluation in vivo in experimental glomerular disease.

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