Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8773029 | Kidney International | 2018 | 18 Pages |
Abstract
Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a major deubiquitinating enzyme of the nervous system and associated with the development of neurodegenerative diseases. We have previously shown that UCH-L1 is found in tubular and parietal cells of the kidney and is expressed de novo in injured podocytes. Since the role of UCH-L1 in the kidney is unknown we generated mice with a constitutive UCH-L1-deficiency to determine its role in renal health and disease. UCH-L1-deficient mice developed proteinuria, without gross changes in glomerular morphology. Tubular cells, endothelial cells, and podocytes showed signs of stress with an accumulation of oxidative-modified and polyubiquitinated proteins. Mechanistically, abnormal protein accumulation resulted from an altered proteasome abundance leading to decreased proteasomal activity, a finding exaggerated after induction of anti-podocyte nephritis. UCH-L1-deficient mice exhibited an exacerbated course of disease with increased tubulointerstitial and glomerular damage, acute renal failure, and death, the latter most likely a result of general neurologic impairment. Thus, UCH-L1 is required for regulated protein degradation in the kidney by controlling proteasome abundance. Altered proteasome abundance renders renal cells, particularly podocytes and endothelial cells, susceptible to injury.
Keywords
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Nephrology
Authors
Victoria Radón, Maire Czesla, Julia Reichelt, Julia Fehlert, Anna Hammel, Alva Rosendahl, Jan-Hendrik Knop, Thorsten Wiech, Ulrich O. Wenzel, Marlies Sachs, Anna T. Reinicke, Rolf A.K. Stahl, Catherine Meyer-Schwesinger,