Ubiquitin C-terminal hydrolase L1 deletion ameliorates glomerular injury in mice with ACTN4-associated focal segmental glomerulosclerosis.
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.
['Read|Naomi C|NC|', 'Gutsol|Alex|A|', 'Holterman|Chet E|CE|', 'Carter|Anthony|A|', 'Coulombe|Josée|J|', 'Gray|Douglas A|DA|', 'Kennedy|Chris R J|CR|']
D000185:Actinin D000818:Animals D003599:Cytoskeleton D004195:Disease Models, Animal D020022:Genetic Predisposition to Disease D005923:Glomerulosclerosis, Focal Segmental D007678:Kidney Glomerulus D051379:Mice D018345:Mice, Knockout D050199:Podocytes D046988:Proteasome Endopeptidase Complex D017384:Sequence Deletion D043222:Ubiquitin Thiolesterase D015854:Up-Regulation
Ubiquitin UCHL1 Podocyte Glomerular disease K256E α-Actinin-4