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TGF-1 Regulates the PINCH-1–Integrin-Linked Kinase–-Parvin Complex in Glomerular Cells

Kyu Yong Jung^*, Ka Chen^*, Matthias Kretzler and Chuanyue Wu^*

^* Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Address correspondence to: Dr. Chuanyue Wu, 707B Scaife Hall, Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261. Phone: 412-648-2350; Fax: 509-561-4062; E-mail: carywu{at}pitt.edu

Received for publication May 1, 2006. Accepted for publication October 2, 2006.

Glomerular damage is a major cause of renal failure. Recent studies suggest that a ternary protein complex that consists of PINCH-1, integrin-linked kinase, and -parvin, cytoplasmic components of cell–extracellular matrix adhesions, plays pivotal roles in regulation of glomerular cell behavior. It is reported here that TGF-1, a key factor in the progression of glomerular failure, regulates the PINCH-1–integrin-linked kinase–-parvin (PIP) complex formation in glomerular podocytes and mesangial cells. Treatment of podocytes with TGF-1 inhibited the PIP complex formation. Forced disruption of the PIP complex in podocytes activated p38 mitogen-activated protein kinase and promoted apoptosis. Importantly, inhibition of p38 mitogen-activated protein kinase, either with a chemical p38 inhibitor (SB202190) or with a dominant negative form of p38, alleviates podocyte apoptosis that is induced by the disruption of the PIP complex. In contrast to an inhibitory role in podocytes, TGF-1 promotes the PIP complex formation in mesangial cells. Thus, TGF-1 regulates the PIP complex in a cell type–dependent manner. Because the PIP complex promotes glomerular mesangial matrix deposition and protects podocytes from apoptosis, the TGF-1–induced up- and downregulation of the PIP complex likely contribute to the pleiotropic effects of TGF-1 on different glomerular cell types and hence the progression of glomerular failure.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673