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Formation and Phosphorylation of the PINCH-1–Integrin Linked Kinase–-Parvin Complex Are Important for Regulation of Renal Glomerular Podocyte Adhesion, Architecture, and Survival

Yanqiang Yang^*, Lida Guo^*, Simone M. Blattner, Peter Mundel, Matthias Kretzler and Chuanyue Wu^*

^* Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Medizinische Poliklinik, Ludwig-Maximilians-University of Munich, Munich, Germany; and Division of Nephrology, Mount Sinai School of Medicine, New York, New York

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; carywu{at}pitt.edu or Dr. Matthias Kretzler, Nephrology Center, University of Munich, Schillerstrasse 42, D-80336 Munich, Germany. Phone: +49-89-5160-3563; Fax: +49-89-2180-7586; E-mail: matthias.kretzler{at}med.uni-muenchen.de

Received for publication December 21, 2004. Accepted for publication March 22, 2005.

Alterations in the cellular architecture, adhesion, and/or loss of glomerular podocytes are causal factors in the development of proteinuria and the progression to end-stage renal failure. With the use of an inducible podocyte differentiation system, it was found that the cellular levels of PINCH-1, integrin linked kinase (ILK), and -parvin, cytoplasmic components of cell–extracellular matrix adhesions, were significantly increased during podocyte differentiation. Concomitantly, an increased amount of the PINCH-1–ILK–-parvin complex was detected in the differentiated, foot process–containing podocytes. Overexpression of the PINCH-1–binding ankyrin repeat domain of ILK but not that of a PINCH-1–binding defective mutant form of the ankyrin domain effectively inhibited the formation of the PINCH-1–ILK–-parvin complex. Disruption of the PINCH-1–ILK–-parvin complex significantly reduced the podocyte–matrix adhesion and foot process formation. Furthermore, a marked increase of apoptosis in the podocytes in which the assembly of the PINCH-1–ILK–-parvin complex was compromised was detected. Inhibition of ILK with a small compound inhibitor also altered podocyte cytoskeleton and increased apoptosis. Finally, it is shown that -parvin is phosphorylated in podocytes. Mutations at the -parvin N-terminal proline-directed serine phosphorylation sites reduced its complex formation with ILK and resulted in defects in podocyte adhesion, architecture, and survival. These results provide important evidence for a crucial role of the PINCH-1–ILK–-parvin complex in the control of podocyte adhesion, morphology, and survival.

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