OverviewThe MGH Program in Glomerular Disease in the Division of Nephrology is founded with the mission:
Glomerular diseases affect several million people in the US alone. They result from intrinsic causes such as inherited defects in podocytes, basement membrane, endothelial cells, as well as the mesangial cells that together comprise the filtration unit of the kidney. Major extrinsic causes of injury are infiltrating leukocytes that accumulate in many inflammatory diseases of the kidney, causing progressive loss of kidney function.
Podocytes are specialized cells of the kidney that form the blood filtration barrier in the glomerulus. Mutations in intrinsic structural and regulatory genes cause changes in podocyte structure and loss of fine processes leading to glomerular disease. Infiltrating leukocytes are major extrinsic causes of injury to glomerular function.
The zebrafish pronephros is highlighted here by staining for the Na+/K+ATPase alpha1 subunit which is abundantly expressed in the bilateral paired pronephric tubules and ducts.
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.
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 two novel genes, the band 4.1/FERM domain gene mosaic eyes, and phospholipase C epsilon, are required in podocytes for proper formation of slit-diaphragm cell-cell junctions. A functional assay of glomerular filtration barrier revealed that absence normal nephrin, podocin, plce, or mosaic eyes expression results in loss of glomerular filtration discrimination and aberrant passage of high molecular weight substances into the glomerlar filtrate.
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