Genes required for podocyte function

Podocytes are specialized cells of the kidney that form the blood filtration barrier in the kidney glomerulus. Request reprint >>

The barrier function of podocytes depends upon the development of specialized cell-cell adhesion complexes called slit-diaphragms that form between podocyte foot processes surrounding glomerular blood vessels. Failure to form the slit-diaphragm results in leakage of high molecular weight proteins into the blood filtrate and urine, a condition called proteinuria.

We have shown that the zebrafish pronephros can be used as an assay system for the development of glomerular function and to identify novel components of the slit-diaphragm. We have characterized the function of the zebrafish homolog of Nephrin, the disease gene associated with the congenital nephritic syndrome of the Finnish type, and Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome. Zebrafish nephrin and podocin are specifically expressed in pronephric podocytes and are required for the development of pronephric podocyte cell structure.

Podocin is expressed at 32 hpf in the nephron primordia prior to fusion at the midline. Later, at 72 hpf, podocin expression is specific to the fully formed podocytes that form the compound glomerulus at the midline.

Ultrastructurally, disruption of nephrin or podocin expression results in a loss of slit-diaphragms at 72 and 96 hours post-fertilization and failure to form normal podocyte foot processes. We have also shown that expression of the band 4.1/FERM domain gene mosaic eyes in podocytes is required for proper formation of slit-diaphragm cell-cell junctions. A functional assay of glomerular filtration barrier revealed that absence normal nephrin, podocin or mosaic eyes expression results in loss of glomerular filtration discrimination and aberrant passage of high molecular weight substances into the glomerular filtrate.

Nephrin expression is restricted to the podocyte layer of the glomerulus at 120hpf.