Proteinuria is a primary clinical symptom of a large number of glomerular diseases
that progress to end-stage renal failure. Podocyte dysfunctions play a fundamental
role in defective glomerular filtration in many common forms of proteinuric kidney
disorders. Since binding of these cells to the basement membrane is mediated by integrins,
we determined the role of integrin-linked kinase (ILK) in podocyte dysfunction and
proteinuria. ILK expression was induced in mouse podocytes by various injurious stimuli
known to cause proteinuria including TGF-beta1, adriamycin, puromycin, and high ambient
glucose. Podocyte ILK was also found to be upregulated in human proteinuric glomerular
diseases. Ectopic expression of ILK in podocytes decreased levels of the epithelial
markers nephrin and ZO-1, induced mesenchymal markers such as desmin, fibronectin,
matrix metalloproteinase-9 (MMP-9), and alpha-smooth muscle actin (alpha-SMA), promoted
cell migration, and increased the paracellular albumin flux across podocyte monolayers.
ILK also induced Snail, a key transcription factor mediating epithelial-mesenchymal
transition (EMT). Blockade of ILK activity with a highly selective small molecule
inhibitor reduced Snail induction and preserved podocyte phenotypes following TGF-beta1
or adriamycin stimulation. In vivo, this ILK inhibitor ameliorated albuminuria, repressed
glomerular induction of MMP-9 and alpha-SMA, and preserved nephrin expression in murine
adriamycin nephropathy. Our results show that upregulation of ILK is a convergent
pathway leading to podocyte EMT, migration, and dysfunction. ILK may be an attractive
target for therapeutic intervention of proteinuric kidney diseases.