title: UCH-L1 induces podocyte hypertrophy in membranous nephropathy by protein accumulation.
abstract: Podocytes are terminally differentiated cells of the glomerular filtration barrier that react with hypertrophy in the course of injury such as in membranous nephropathy (MGN). The neuronal deubiquitinase ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed and activated in podocytes of human and rodent MGN. UCH-L1 regulates the mono-ubiquitin pool and induces accumulation of poly-ubiquitinated proteins in affected podocytes. Here, we investigated the role of UCH-L1 in podocyte hypertrophy and in the homeostasis of the hypertrophy associated "model protein" p27(Kip1). A better understanding of the basic mechanisms leading to podocyte hypertrophy is crucial for the development of specific therapies in MGN. In human and rat MGN, hypertrophic podocytes exhibited a simultaneous up-regulation of UCH-L1 and of cytoplasmic p27(Kip1) content. Functionally, inhibition of UCH-L1 activity and knockdown or inhibition of UCH-L1 attenuated podocyte hypertrophy by decreasing the total protein content in isolated glomeruli and in cultured podocytes. In contrast, UCH-L1 levels and activity increased podocyte hypertrophy and total protein content in culture, specifically of cytoplasmic p27(Kip1). UCH-L1 enhanced cytoplasmic p27(Kip1) levels by nuclear export and decreased poly-ubiquitination and proteasomal degradation of p27(Kip1). In parallel, UCH-L1 increased podocyte turnover, migration and cytoskeletal rearrangement, which are associated with known oncogenic functions of cytoplasmic p27(Kip1) in cancer. We propose that UCH-L1 induces podocyte hypertrophy in MGN by increasing the total protein content through altered degradation and accumulation of proteins such as p27(Kip1) in the cytoplasm of podocytes. Modification of both UCH-L1 activity and levels could be a new therapeutic avenue to podocyte hypertrophy in MGN.
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Frithjof
authors.initials: F
authors.lastname: Lohmann
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marlies
authors.initials: M
authors.lastname: Sachs
authors.affiliation: Department of Internal Medicine, Nephrology, Asklepios Klinikum Barmbek, Hamburg, Germany.
authors.forename: Tobias N
authors.initials: TN
authors.lastname: Meyer
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Sievert
authors.affiliation: Institute of Physiology and Division of Nephrology, University of Zurich, Switzerland.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.affiliation: Department of Pathology, Division of Renal Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wiech
authors.affiliation: Institute of Physiology and Division of Nephrology, University of Zurich, Switzerland.
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Division of Hematology, University Hospital Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: R A K
authors.initials: RA
authors.lastname: Stahl
authors.affiliation: Department of Internal Medicine, Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: c.meyer-schwesinger@uke.uni-hamburg.de.
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D050199:Podocytes / Q000201:enzymology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: Hypertrophy; Membranous nephropathy; Passive Heymann nephritis; Proteasomal degradation; Ubiquitin C-terminal hydrolase-L1; p27(Kip1)