new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies

• Published in: The Journal of pathology Vol. 217; no. 3; pp. 452 - 464
• Main Authors: Meyer-Schwesinger, C, Meyer, TN, Münster, S, Klug, P, Saleem, M, Helmchen, U, Stahl, RAK
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-02-2009
• Subjects: Actinin - analysis; Actinin - metabolism; Case-Control Studies; Cells, Cultured; glomerulonephritis; Humans; Immunohistochemistry; Kidney Diseases - metabolism; Kidney Diseases - pathology; Membrane Proteins - analysis; Membrane Proteins - metabolism; Microscopy, Confocal; PGP 9.5; podocyte injury; Podocytes - metabolism; Podocytes - pathology; protein degradation and internalization; Reverse Transcriptase Polymerase Chain Reaction; Ubiquitin - analysis; Ubiquitin - metabolism; ubiquitin modification; Ubiquitin Thiolesterase - physiology; UCH-L1
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2446

Glomerular epithelial cell (podocyte) injury is characterized by foot process retraction, slit diaphragm reorganization, and degradation of podocyte-specific proteins. However, the mechanisms underlying podocyte injury are largely unknown. The ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a key modulator of ubiquitin modification in neurons. Like neurons, UCH-L1 expression was associated with an undifferentiated status in cultured human podocytes, whereas differentiation and arborization decreased UCH-L1 and monoUb expression. Inhibition of UCH-L1 induced time and concentration-dependent process formation with α-actinin-4 distribution to the cell membrane and processes. An immunohistochemical approach was used to evaluate whether UCH-L1 expression was associated with podocyte injury in 15 different human glomerular diseases. Whereas normal kidneys expressed no UCH-L1 and little ubiquitin, a subset of human glomerulopathies associated with podocyte foot process effacement (membranous nephropathy, SLE class V, FSGS) de novo expressed UCH-L1 in podocyte cell bodies, nuclei, and processes. Interestingly, UCH-L1 expression correlated with podocyte ubiquitin content and internalization of the podocyte-specific proteins nephrin and α-actinin-4. In contrast, minimal change glomerulonephritis, a reversible disease, demonstrated minimal UCH-L1 and ubiquitin expression with intact α-actinin-4 but internalized nephrin. Glomerular kidney diseases typically not associated with foot process effacement (SLE class IV, ANCA+ necrotizing GN, amyloidosis, IgA nephritis) expressed intermediate to no UCH-L1 and ubiquitin. These studies show a role for UCH-L1 and ubiquitin modification in podocyte differentiation and injury. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.