|ZFIN ID: ZDB-PUB-180119-1|
The von Hippel-Lindau Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae
van Rooijen, E., van de Hoek, G., Logister, I., Ajzenberg, H., Knoers, N.V.A.M., van Eeden, F., Voest, E.E., Schulte-Merker, S., Giles, R.H.
|Source:||Nephron 138(4): 310-323 (Journal)|
|Registered Authors:||Logister, Ive, Schulte-Merker, Stefan, van Eeden, Freek, van Rooijen, Ellen|
|Keywords:||Vesicle trafficking, Hypoxia, Kidney integrity, Pronephros , Zebrafish, von Hippel-Lindau|
|PubMed:||29342457 Full text @ Nephron|
van Rooijen, E., van de Hoek, G., Logister, I., Ajzenberg, H., Knoers, N.V.A.M., van Eeden, F., Voest, E.E., Schulte-Merker, S., Giles, R.H. (2018) The von Hippel-Lindau Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae. Nephron. 138(4):310-323.
Background von Hippel-Lindau (VHL) disease is characterized by the development of benign and malignant tumours in many organ systems, including renal cysts and clear cell renal cell carcinoma. It is not completely understood what underlies the development of renal pathology, and the use of murine Vhl models has been challenging due to limitations in disease conservation. We previously described a zebrafish model bearing inactivating mutations in the orthologue of the human VHL gene.
Methods We used histopathological and functional assays to investigate the pronephric and glomerular developmental defects in vhl mutant zebrafish, supported by human cell culture assays.
Results Here, we report that vhl is required to maintain pronephric tubule and glomerulus integrity in zebrafish embryos. vhl mutant glomeruli are enlarged, cxcr4a+ capillary loops are dilated and the Bowman space is widened. While we did not observe pronephric cysts, the cells of the proximal convoluted and anterior proximal straight tubule are enlarged, periodic acid schiff (PAS) and Oil Red O positive, and display a clear cytoplasm after hematoxylin and eosine staining. Ultrastructural analysis showed the vhl-/- tubule to accumulate large numbers of vesicles of variable size and electron density. Microinjection of the endocytic fluorescent marker AM1-43 in zebrafish embryos revealed an accumulation of endocytic vesicles in the vhl mutant pronephric tubule, which we can recapitulate in human cells lacking VHL.
Conclusions Our data indicates that vhl is required to maintain pronephric tubule and glomerulus integrity during zebrafish development, and suggests a role for VHL in endocytic vesicle trafficking.