Integrin-linked kinase (ILK) has been implicated in the pathogenesis of 
proteinuria and congenital nephrotic syndrome. However, the function of ILK in 
glomerular podocyte in a physiologic setting remains unknown. In this study, a 
mouse model was generated in which ILK gene was selectively disrupted in 
podocytes by using the Cre-LoxP system. Podocyte-specific ablation of ILK 
resulted in heavy albuminuria, glomerulosclerosis, and kidney failure, which led 
to animal death beginning at 10 wk of age. Podocyte detachment and apoptosis 
were not observed at 4 wk of age, when albuminuria became prominent, indicating 
that they are not the initial cause of proteinuria. Electron microscopy revealed 
an early foot process effacement, as well as morphologic abnormality, in 
ILK-deficient podocytes. ILK deficiency caused an aberrant distribution of 
nephrin and alpha-actinin-4 in podocytes, whereas the localization of podocin 
and synaptopodin remained relatively intact. Co-immunoprecipitation demonstrated 
that ILK physically interacted with nephrin to form a ternary complex, and 
alpha-actinin-4 participated in ILK/nephrin complex formation. Therefore, ILK 
plays an essential role in specifying nephrin and alpha-actinin-4 distribution 
and in maintaining the slit diaphragm integrity and podocyte architecture. These 
results also illustrate that the integrin and slit diaphragm signals in 
podocytes are intrinsically coupled through an ILK-dependent mechanism.