title: A new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies.
abstract: 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 alpha-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 alpha-actinin-4. In contrast, minimal change glomerulonephritis, a reversible disease, demonstrated minimal UCH-L1 and ubiquitin expression with intact alpha-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.
authors.affiliation: Department of Internal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany. c.meyer-schwesinger@ uke.uni-hamburg.de
authors.forename: C
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.forename: T N
authors.initials: TN
authors.lastname: Meyer
authors.forename: S
authors.initials: S
authors.lastname: Münster
authors.forename: P
authors.initials: P
authors.lastname: Klug
authors.forename: M
authors.initials: M
authors.lastname: Saleem
authors.forename: U
authors.initials: U
authors.lastname: Helmchen
authors.forename: R A K
authors.initials: RA
authors.lastname: Stahl
mesh_terms: D000185:Actinin / Q000032:analysis / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D018613:Microscopy, Confocal; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000502:physiology*
chemical_list: C111453:ACTN4 protein, human; D008565:Membrane Proteins; C482860:UCHL1 protein, human; D025801:Ubiquitin; C113267:nephrin; D000185:Actinin; D043222:Ubiquitin Thiolesterase