Ubiquitin C-Terminal Hydrolase-L1 Activity Induces Polyubiquitin Accumulation in Podocytes and Increases Proteinuria in Rat Membranous Nephropathy
| Autor: | Friedrich Thaiss, Rolf A.K. Stahl, Udo Helmchen, Tobias N. Meyer, Stefan Balabanov, Silvia Münster, Henning Sievert, Eva-Maria Klupp, Elion Hoxha, Lucie Carrier, Marlies Sachs, Catherine Meyer-Schwesinger |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Proteasome Endopeptidase Complex medicine.medical_specialty Blotting Western Ubiquitin C-Terminal Hydrolase Glomerulonephritis Membranous Pathology and Forensic Medicine Podocyte Rats Sprague-Dawley Ubiquitin Membranous nephropathy Internal medicine medicine Animals Humans Polyubiquitin biology Podocytes Reverse Transcriptase Polymerase Chain Reaction Regular Article Ubiquitin homeostasis Glomerulonephritis Biological activity medicine.disease Immunohistochemistry Ubiquitin carboxy-terminal hydrolase L1 Rats Cell biology Proteinuria Endocrinology medicine.anatomical_structure biology.protein Ubiquitin Thiolesterase |
| Zdroj: | The American Journal of Pathology. 178:2044-2057 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2011.01.017 |
| Popis: | Ubiquitin C-terminal hydrolase L1 (UCH-L1), a key protease of the ubiquitin-proteasome system (UPS), is associated with neurodegenerative diseases and cancer. Recently, de novo expression of UCH-L1 was described in podocytes in patients with membranous nephropathy (MN), in which UCH-L1 expression correlated with increased ubiquitin content. The objective of the present study was to investigate the role of UCH-L1 in ubiquitin homeostasis and proteasomal degradation in a rat model of MN. After disease induction, UCH-L1 expression increased in podocytes and coincided with decreased glomerular monoubiquitin content. After an initial increase in proteasomal activity, the UPS was impaired. In addition to an increase of ubiquitin in podocytes, aggregates were observed 1 year after disease induction, as in MN in human beings. Inhibition of UCH-L1 hydrolase function in MN reduced UPS impairment and ameliorated proteinuria. In contrast, inhibition of proteasomal activity enhanced UPS impairment, resulting in increased proteinuria. Stable UCH-L1 overexpression in cultured podocytes resulted in accumulation of monoubiquitin and polyubiquitin proteins. In contrast, stable knock-down of UCH-L1 reduced monoubiquitin and polyubiquitin proteins and significantly increased proteasomal activity, indicating that the observed effects in rat MN also occurred in cultured podocytes. These data demonstrate that UCH-L1 activity results in polyubiquitin accumulation, proteasome inhibition, and disease aggravation in experimental models of MN. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|