Murine Epsins Play an Integral Role in Podocyte Function

Significance Statement When podocytes are injured, foot processes efface and detach, leading to severe proteinuria. Endocytic trafficking maintains the integrity of this crucial glomerular interface. Epsins, a family of membrane proteins, assist in the endocytosis and also take part in cell signaling. Mice that have lost podocyte-associated epsins develop proteinuria and kidney failure, due to diminished activity of the transcription factor serum response factor (SRF), which reduces cell division control protein 42 homolog activation and β 1 integrin expression. Podocyte-specific Srf knockout mice also demonstrate proteinuria and kidney failure. These findings suggest that, in podocytes, epsins are required to coordinate a proper signaling platform, beyond their known endocytic properties. Background Epsins, a family of evolutionarily conserved membrane proteins, play an essential role in endocytosis and signaling in podocytes. Methods Podocyte-specific Epn1 , Epn2 , Epn3 triple-knockout mice were generated to examine downstream regulation of serum response factor (SRF) by cell division control protein 42 homolog (Cdc42). Results Podocyte-specific loss of epsins resulted in increased albuminuria and foot process effacement. Primary podocytes isolated from these knockout mice exhibited abnormalities in cell adhesion and spreading, which may be attributed to reduced activation of cell division control protein Cdc42 and SRF, resulting in diminished β 1 integrin expression. In addition, podocyte-specific loss of Srf resulted in severe albuminuria and foot process effacement, and defects in cell adhesion and spreading, along with decreased β 1 integrin expression. Conclusions Epsins play an indispensable role in maintaining properly functioning podocytes through the regulation of Cdc42 and SRF-dependent β 1 integrin expression.