Characterization of Molecules Involved in Maintenance of the Filtration Slits and Foot Processes of the Glomerulus Normal and Nephrotic

The glomerular epithelial cells or podocytes are unusual polarized epithelial cells that are organized into characteristic interdigitating foot processes bridged by filtration slits. In kidney diseases associated with proteinuria the typical foot process and slit arrangement is lost. Two of the molecules that are essential for maintaining the normal foot process and slit architecture of the glomerulus are podocalyxin and nephrin. Defining the functions and interactions of these molecules are the focus of two ongoing projects in the lab.

Podocalyxin: We have shown that the ectodomain of podocalyxin acts as an anti-adhesin that serves to maintain the filtration slits open, and the cytoplasmic tail of podocalyxin is attached to the actin cytoskeleton through NHERF2 and ezrin. We are now attempting to define the molecular mechanisms involved in the regulation of the podocyte’s unique shape by podocalyxin. Our approach combines work on the normal and pathologic glomeruli and studies on MDCK cell lines expressing podocalyxin and podocalyxin mutants.

Nephrin is an immunoglobulin family protein concentrated in the slit diaphragms that attach the foot processes of podocytes to one another. Nephrin was identified as an essential component of the filtration slit diaphragms based on the characterization of the defective gene in congenital nephrosis of the Finnish type in humans. The functions and interactions of nephrin in the slit diaphragm are not yet fully understood. Our work focuses on the identification and characterization of junctional proteins, cytoskeletal proteins and signaling molecules that bind to nephrin.

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