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Zebrafish Model of Cystic Kidney Disease

Posted May 28 2009 12:00am
For the research component of my Nephrology fellowship, I've chosen an unorthodox route:  I am using the zebrafish as a model organism for the study of kidney disease.  

The zebrafish system has a number of advantages.  First, a single male/female pair can produce hundreds of eggs overnight, thus opening the door for great genetic studies.  It's akin to the fruit fly in this respect, but because the zebrafish is a vertebrate and the fruit fly is not, the zebrafish genome is much more similar to the human genome.  Zebrafish embryos are completely transparent, and thus you can watch their kidneys develop in real-time.  The early zebrafish kidney (called the pronephros) first appears within 24-48 hours, so experiments can be done with a rapidity unmatched in mice.  Furthermore, the zebrafish pronephros is much more simple than the mammalian kidney:  in fact, it consists of a single nephron!!  Despite this simplicity, the nephron contains discrete proximal, distal, and collecting duct domains which appear to be very similar to their mammalian counterparts.  

I'm presently using the zebrafish system as a model of cystic kidney disease.  For example, knocking down the genes for PKD1 and PKD2 (mutations in which result in ADPKD in humans) result in glomerular cyst formation within the single nephron of the zebrafish.  I am presently using this system in order to identify new genes which may be part of the PKD1/PKD2 pathway.  For instance,  here is an example of a gene I knocked down which interestingly results in dilatation of the pronephric ducts (shown by arrows) and cysts which form in the single glomerulus (arrowheads, looks kind of like a big bubble). 

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