Integrin linked kinase as a candidate downstream effector in proteinuria

The kidney glomerulus is responsible for the generation of a protein-free ultrafiltrate. After injury, it shows a characteristic, uniform response leading to progressive renal failure. Recent studies of hereditary proteinuric diseases have revealed mutations in molecules involved in podocyte cell-cell and cell-matrix interaction. Associated cellular signaling events activated in proteinuria have not been analyzed so far. To identify proteinuria-induced molecules, we used mRNA differential display in glomeruli from children with congenital nephrotic syndrome of the Finnish type. An increase in integrin linked kinase (ILK) mRNA, beta (1)-integrin coupled serine threonine kinase, was identified. Observations suggest a role for ILK in glomerular failure. An up-regulation of glomerular and Single-podocyte ILK mRNA was found in two murine models of proteinuria. In cultured podocytes, integrin attachment to matrix inhibited ILK activity and podocyte damage with puromycin activated ILK. Stable overexpression of ILK in murine podocytes caused reduced matrix adhesion and led to considerable phenotype alteration compared with expression of a kinase-defective ILK, paralleling aspects of in vivo podocyte damage. These results are consistent with ILK as a relevant player in the orchestration of podocyte matrix interaction and a candidate downstream regulator of podocyte permselectivity in glomerular diseases.