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Am J Physiol Renal Physiol 293: F1746-F1750, 2007. First published August 15, 2007; doi:10.1152/ajprenal.00009.2007
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INNOVATIVE METHODOLOGY

Rapid screening of glomerular slit diaphragm integrity in larval zebrafish

Dirk M. Hentschel,1,4 Michael Mengel,2 Lisa Boehme,3 Fabian Liebsch,3 Caroline Albertin,1 Joseph V. Bonventre,1 Hermann Haller,3 and Mario Schiffer3,4

1Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; 2Department of Pathology and 3Division of Nephrology, Department of Medicine, Hannover Medical School, Hannover, Germany; and 4Mount Desert Island Biological Laboratories, Salisbury Cove, Maine

Submitted 4 January 2007 ; accepted in final form 14 August 2007

Gene array-type experiments have identified large numbers of genes thought to be important for the integrity of the glomerular slit diaphragm. Confirmation of individual proteins has been limited by the expenses and time involved in generating transgenic or knockout mice for each candidate. We present a functional screening assay based on the clearance of a 70-kDa fluorescent dextran in another vertebrate system that is rapid and low in cost. In the pronephric glomerulus of larval zebrafish, we have demonstrated quantifiable loss of slit diaphragm integrity in a zebrafish model of puromycin aminonucleoside (PA) toxicity. In addition, after knockdown of CD2-associated protein (CD2AP) and podocin, two well-characterized genetic contributors to podocyte differentiation in mammals, we observed glomerular loss of serum macromolecules similar to that seen in mammalian kidneys with inborn mutations in these genes. Increased filtration of 70-kDa FITC-labeled dextran correlates with effacement of podocyte foot processes in ultrastructural analysis. These findings document the value of the zebrafish model in genomics and pharmacological screening applications.

podocyte; nephrotic syndrome; puromycin aminonucleoside; CD2-associated protein; podocin


Address for reprint requests and other correspondence: D. M. Hentschel, Renal Division, Dept. of Medicine, Brigham and Women's Hospital, HIM-550, 4 Blackfan Circle, Boston, MA 02115 (e-mail: dhentschel{at}partners.org); and M. Schiffer, Division of Nephrology, Dept. of Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany (e-mail: schiffer.mario{at}mh-hannover.de)






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