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Cytoskeletal Rearrangement and Signal Transduction in TGF-1–Stimulated Mesangial Cell Collagen Accumulation

Susan C. Hubchak^*, Constance E. Runyan^*, Jeffrey I. Kreisberg and H. William Schnaper^*

*Department of Pediatrics, Northwestern University Medical School, and Children’s Memorial Institute for Education and Research, Chicago, Illinois; and Department of Surgery, University of Texas Health Science Center at San Antonio, and Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, Texas.

Correspondence to Susan C. Hubchak, Northwestern University Medical School, W-140 Pediatrics, 303 E. Chicago Avenue, Ward 12-112, Chicago, IL 60611-3008. Phone: 312-503-2918; Fax: 312-503-1181;

ABSTRACT. TGF-1 has been implicated in glomerular extracellular matrix accumulation, although the precise cellular mechanism(s) by which this occurs is not fully understood. The authors have previously shown that the Smad signaling pathway is present and functional in human glomerular mesangial cells and plays a role in activating type I collagen gene expression. It also was determined that TGF-1 activates ERK mitogen-activated protein kinase in mesangial cells to enhance Smad activation and collagen expression. Here, it was shown that TGF-1 rapidly induces cytoskeletal rearrangement in human mesangial cells, stimulating smooth muscle -actin detection in stress fibers and promoting focal adhesion complex assembly and redistribution. Disrupting the actin cytoskeleton with cytochalasin D (Cyto D) selectively decreased basal and TGF-1–induced cell-layer collagen I and IV accumulation. The balance of matrix metalloproteinases (MMP) and inhibitors was altered by Cyto D or TGF-1 alone, increasing MMP activity, increasing MMP-1 expression, and decreasing tissue inhibitor of matrix metalloproteinase-2 expression. Cyto D also decreased basal and TGF-1–stimulated 1(I) collagen mRNA but did not inhibit TGF-–stimulated 1(IV) mRNA expression. A similar decrease in 1(I) mRNA expression caused by the actin polymerization inhibitor latrunculin B was partially blocked by the addition of jasplakinolide, which promotes actin assembly. The Rho-family GTPase inhibitor C. difficile toxin B or the Rho-associated kinase inhibitor Y-27632 also blocked TGF-1–stimulated 1(I) mRNA expression. Cytoskeletal disruption reduced Smad2 phosphorylation but had little effect on mRNA stability, TGF- receptor number, or receptor affinity. Thus, TGF-1–mediated collagen I accumulation is associated with cytoskeletal rearrangement and Rho-GTPase signaling. E-mail: s-hubchak@northwestern.edu

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