Snail is
a DNA-binding molecule that plays a pivotal role in regulating cell adhesion and epithelial to mesenchymal transition. Visceral epithelial cells (podocytes) in kidney glomeruli form a sophisticated cell-cell junction called a slit diaphragm that prevents the loss of
plasma protein during ultrafiltration.
Nephrin, located in the slit diaphragm and critical for maintaining the integrity of this structure, belongs to the class of
cell adhesion molecules of the
immunoglobulin super-family. As previously reported, the transcriptional activity of
nephrin is a determinant of the integrity of the slit diaphragm in
puromycin aminonucleoside (PAN)
nephrosis rats. Here, we examined the role of Snail in
nephrin expression. In accordance with the downregulation of
nephrin in PAN
nephrosis rats, Snail was upregulated in vivo and its
DNA-binding activity was stimulated in injured podocytes while normal podocytes did not express Snail. An in vitro study demonstrated that Snail bound to E-box motifs in a specific segment of the rat
nephrin gene repressed the transcription of
nephrin and downregulated
nephrin protein. We also found that the expression level of Snail in injured podocytes was regulated by GSK3, which is known to phosphorylate Snail and induce its proteolysis. Pharmacological in vitro and in vivo inhibition studies of GSK3 suggested that GSK3 activity decreased in injured podocytes and this change partially contributed to the decrease in
nephrin and increase in Snail and
proteinuria. Concordantly, we found that Wnt-2 was upregulated in injured podocytes and activated the Wnt canonical pathway. As the Wnt canonical pathway inactivates GSK3, it is likely that Wnt-2 accounts for the accumulation of Snail in injured podocytes. In conclusion, Snail is a key molecule, which perturbs the integrity of the slit diaphragm through transcriptional repression of
nephrin under pathological conditions. Wnt-GSK3 pathway participates in this mechanism.