title: Ubiquitin C-terminal hydrolase L1 deletion ameliorates glomerular injury in mice with ACTN4-associated focal segmental glomerulosclerosis.
abstract: Renal ubiquitin C-terminal hydrolase L1 (UCHL1) is upregulated in a subset of human glomerulopathies, including focal segmental glomerulosclerosis (FSGS), where it may serve to promote ubiquitin pools for degradation of cytotoxic proteins. In the present study, we tested whether UCHL1 is expressed in podocytes of a mouse model of ACTN4-associated FSGS. Podocyte UCHL1 protein was detected in glomeruli of K256E-ACTN4(pod+)/UCHL1+/+ mice. UCHL1+/- mice were intercrossed with K256E-ACTN4(pod+) mice and monitored for features of glomerular disease. 10-week-old K256E-ACTN4(pod+)/UCHL1-/- mice exhibited significantly ameliorated albuminuria, glomerulosclerosis, tubular pathology and blood pressure. Interestingly, while UCHL1 deletion diminished both tubular and glomerular apoptosis, WT1-positive nuclei were unchanged. Finally, UCHL1 levels correlated positively with poly-ubiquitinated proteins but negatively with K256E-α-actinin-4 levels, implying reduced K256E-α-actinin-4 proteolysis in the absence of UCHL1. Our data suggest that UCHL1 upregulation in ACTN4-associated FSGS fuels the proteasome and that UCHL1 deletion may impair proteolysis and thereby preserve K256E/wt-α-actinin-4 heterodimers, maintaining podocyte cytoskeletal integrity and protecting the glomerular filtration barrier.
authors.affiliation: Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Read
authors.affiliation: Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Gutsol
authors.affiliation: Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Chet E
authors.initials: CE
authors.lastname: Holterman
authors.affiliation: Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Carter
authors.affiliation: Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Coulombe
authors.affiliation: Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Gray
authors.affiliation: Kidney Research Centre, The Ottawa Hospital, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: ckennedy@uottawa.ca.
authors.forename: Chris R J
authors.initials: CR
authors.lastname: Kennedy
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C491752:Actn4 protein, mouse; D000185:Actinin; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Glomerular disease; K256E; Podocyte; UCHL1; Ubiquitin; α-Actinin-4