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TGF-1–Mediated Inhibition of HK-2 Cell Migration

Institute of Nephrology, University of Wales College of Medicine, Cardiff, Wales.

Correspondence to Dr. A. O. Phillips, Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN. Phone: 44-2920-748411; Fax: 44-2920-748470;

ABSTRACT. Restoration of proximal tubular cell (PTC) integrity and function after ischemic injury involves cell proliferation and migration. Hypoxia is a known stimulus for PTC TGF-1 synthesis. This study examines the effect of TGF-1 on PTC migration. A model of PTC injury was used consisting of mechanically wounding a monolayer of HK2 cells followed by repopulation of the denuded area by time lapse photomicroscopy. Repopulation was the result of cell migration but not proliferation. Addition of TGF-1 led to a marked inhibition of cell migration increased expression of paxillin and vincullin and their incorporation into dense focal adhesion plaques. This was associated with increased association of focal adhesion components with the f-actin cytoskeleton. There was also increased 3 integrin expression and increased synthesis of the matrix component fibronectin. The effect on migration and focal adhesion reorganisation was abrogated by inhibitors of the RhoA downstream target ROCK, suggesting that signaling events resulting from altered 3 integrin expression initiate the TGF-1 response. These results suggest that, by inhibition of cell migration, increased expression of TGF-1 after ischemia delays recovery of proximal tubule structure and function. We speculate that this may contribute to permanent alteration in renal tubular function after severe ischemic injury. E-mail: PhillipsAO@cf.ac.uk

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