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Am J Physiol Renal Physiol. 2017 Apr 1;312(4):F702-F715. doi: 10.1152/ajprenal.00197.2016. Epub 2017 Feb 1.

USP40 gene knockdown disrupts glomerular permeability in zebrafish.

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Department of Pediatrics, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Division of Matrix Biology, Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Laboratory of Cell Regulation, Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Medical Innovation Center, TMK Project, Kyoto University Graduate School of Medicine, Kyoto, Japan; and.
Laboratory of Biochemistry, Human Health Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Pediatrics, Kyorin University School of Medicine, Mitaka, Tokyo, Japan;


Unbiased 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-small-interfering RNA transfection revealed significant reduction of nestin. In a rat model of minimal-change nephrotic syndrome, USP40 expression was apparently reduced, which was also associated with the reduction of nestin. Zebrafish morphants lacking Usp40 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/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.


development; podocyte; ubiquitin-specific protease; ubiquitin-specific protease 40

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