|ZFIN ID: ZDB-PUB-170204-11|
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USP40 gene knockdown disrupts glomerular permeability in zebrafish
Takagi, H., Nishibori, Y., Katayama, K., Katada, T., Takahashi, S., Kiuchi, Z., Takahashi, S.I., Kamei, H., Kawakami, H., Akimoto, Y., Kudo, A., Asanuma, K., Takematsu, H., Yan, K.
|Source:||American journal of physiology. Renal physiology 312(4): F702-F715 (Journal)|
|Keywords:||development, glomerular endothelial cell, podocyte, ubiquitin specific protease|
|PubMed:||28148530 Full text @ Am. J. Physiol. Renal Physiol.|
Takagi, H., Nishibori, Y., Katayama, K., Katada, T., Takahashi, S., Kiuchi, Z., Takahashi, S.I., Kamei, H., Kawakami, H., Akimoto, Y., Kudo, A., Asanuma, K., Takematsu, H., Yan, K. (2017) USP40 gene knockdown disrupts glomerular permeability in zebrafish. American journal of physiology. Renal physiology. 312(4):F702-F715.
ABSTRACTUnbiased transcriptome profiling and functional genomics approaches have identified ubiquitin specific protease 40 (USP40) as a highly specific glomerular transcript. This gene product remains uncharacterized, and its biological function is completely unknown. Here, we showed that mouse and rat glomeruli exhibit specific expression of the USP40 protein, which migrated at 150 kDa and was exclusively localized in the podocyte cytoplasm of the adult kidney. Double-labeling immunofluorescence staining and confocal microscopy analysis of fetal and neonate kidney samples revealed that USP40 was also expressed in the vasculature, including in glomerular endothelial cells at the premature stage. USP40 in cultured glomerular endothelial cells and podocytes was specifically localized to the intermediate filament protein: nestin. In glomerular endothelial cells, immunoprecipitation confirmed actual protein-protein binding of USP40 with nestin, and USP40-siRNA transfection revealed significant reduction of nestin. In rat model of minimal change nephrotic syndrome, apparent reduction of USP40 in the diseased podocytes at the proteinuric stage, which was also associated with the reduction of nestin. Morphants lacking USP40 in zebrafish exhibited disorganized glomeruli with the reduction of the cell junction in the endothelium and foot process effacement in the podocytes. Permeability studies in these zebrafish morphants demonstrated a disruption of the selective glomerular permeability filter. These data indicate that USP40 is a novel protein that might play a crucial role in glomerulogenesis and the glomerular integrity after birth through the modulation of intermediate filament protein homeostasis.