New data suggest that loss of nephrin tyrosine phosphorylation in podocytes is a driver of renal disease progression. Researcher Nina Jones and colleagues report that this phosphorylation is required for stabilization and repair of podocyte foot process architecture after injury.
Nephrin is a transmembrane protein that links the slit diaphragm to the actin cytoskeleton of podocytes. Several signalling proteins, including the cytoskeletal adaptor Nck, interact with phosphorylated nephrin. “We proposed that these dynamic connections are important for cells such as podocytes to maintain their flexible and essential shape,” explains Jones. “Our group and others have previously shown that nephrin tyrosine phosphorylation is reduced in human renal disease and in experimental kidney injury, so we decided to test whether this reduction was a cause or a consequence of renal disease.”
nephrin tyrosine phosphorylation is reduced in human renal disease
To investigate the effect of phosphonephrin signalling on podocyte morphology, Jones and colleagues generated homozygous and heterozygous knockin mice with mutations in nephrin at three sites that disrupt tyrosine phosphorylation and Nck1/2 binding. The homozygous mice developed severe proteinuria, structural alterations in the glomerular basement membrane and podocyte foot process effacement, whereas hetrozygous mice developed a similar phenotype with later onset. Moreover, compared with wild-type mice, the knockin mice showed delayed recovery in reversible models of renal injury.
“There is some speculation that an increase in nephrin phosphorylation might promote renal injury — in various injury models some sites are phosphorylated, whereas others are dephosphorylated — however, our new knockin mouse model really solidifies the hypothesis that overall loss of nephrin phosphorylation is causative,” says Jones. She suggests that podocytes that lack phosphorylated nephrin cannot bind Nck to properly engage the cytoskeletal machinery, and therefore cannot uphold or restore their foot process architecture after kidney injury.
The researchers are now interested in developing strategies to selectively preserve or enhance nephrin tyrosine phosphorylation. They hope that these approaches, which directly target the podocyte actin skeleton, could help to preserve glomerular filtration barrier function in proteinuric kidney disease.
New, L. A. et al. Nephrin tyrosine phosphorylation is required to stabilize and restore podocyte foot process architecture. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2015091048
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Carney, E. Phosphorylation preserves podocytes. Nat Rev Nephrol 12, 197 (2016). https://doi.org/10.1038/nrneph.2016.17
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