USP40 gene knockdown disrupts glomerular permeability in zebrafish.

Area of Science:

• Nephrology
• Molecular Biology
• Genomics

Background:

• Ubiquitin-specific protease 40 (USP40) is a newly identified glomerular transcript with an unknown biological function.
• Previous studies have not characterized the role of USP40 in kidney physiology.

Purpose of the Study:

• To investigate the expression, localization, and function of USP40 in the kidney glomerulus.
• To elucidate the role of USP40 in glomerulogenesis and maintaining glomerular integrity.

Main Methods:

• Immunofluorescence staining and confocal microscopy in mouse, rat, and zebrafish models.
• USP40 small-interfering RNA transfection in cultured cells.
• Immunoprecipitation assays.
• Zebrafish morphant studies to assess glomerular structure and function.

Main Results:

• USP40 protein is specifically expressed in adult mouse and rat glomeruli, localized to podocyte cytoplasm.
• USP40 interacts with nestin, an intermediate filament protein, in glomerular endothelial cells and podocytes.
• USP40 reduction in a nephrotic syndrome model correlated with decreased nestin levels.
• Usp40-deficient zebrafish exhibited glomerular disorganization, endothelial cell junction loss, podocyte foot process effacement, and impaired glomerular filtration.

Conclusions:

• USP40 is a novel protein essential for glomerular development and postnatal integrity.
• USP40 regulates glomerular structure and function through modulation of intermediate filament protein homeostasis.
• USP40 plays a critical role in maintaining the selective permeability of the glomerular filter.