Regulation of fibronectin matrix deposition and cell proliferation by the PINCH‐ILK‐CH‐ILKBP complex

Alteration in renal glomerular mesangial cell growth and fibronectin matrix deposition is a hallmark of glomerulosclerosis, which ultimately leads to end‐stage renal failure. We have previously shown that the expression of integrin‐linked kinase (ILK), a cytoplasmic component of the cell–extracellular matrix contacts, is increased in mesangial cells in human patients with diabetic nephropathy. We show here that ILK forms a complex with PINCH and CH‐ILKBP in primary mesangial cells, which are co‐clustered at fibrillar adhesions, sites that are involved in fibronectin matrix deposition. To investigate functional significance of the PINCH‐ILK‐CHILKBP complex formation, we expressed the PINCH‐binding N‐terminal fragment and the CHILKBP‐binding C‐terminal fragment of ILK, respectively, in mesangial cells by using an adenoviral expression system. Overexpression of either the N‐terminal fragment or the C‐terminal fragment of ILK effectively inhibited the PINCH‐ILK‐CH‐ILKBP complex formation. Inhibition of the PINCH‐ILK‐CH‐ILKBP complex formation significantly reduced fibronectin matrix deposition and inhibited cell proliferation. These results indicate that the PINCH‐ILKCH‐ILKBP complex is critically involved in the regulation of mesangial fibronectin matrix deposition and cell proliferation, and suggest that it may potentially serve as a useful target in the therapeutic control of progressive renal failure and other pathological processes involving abnormal cell proliferation and fibronectin matrix deposition.