Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis
| Autor: | Christoph Kuppe, Marcus J. Moeller, Jeffrey D. Singer, Catherina A. Cuevas, Turgay Saritas, Rafael Kramann, Mohammed Z. Ferdaus, James A. McCormick, Jürgen Floege |
|---|---|
| Přispěvatelé: | Internal Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
NF-E2-Related Factor 2 lcsh:Medicine Fluorescent Antibody Technique Article Cell Line Kidney Tubules Proximal 03 medical and health sciences Mice 0302 clinical medicine Fibrosis medicine Renal fibrosis Animals Genetic Predisposition to Disease Renal Insufficiency lcsh:Science Genetic Association Studies Cell Proliferation Mice Knockout Kidney Multidisciplinary Kelch-Like ECH-Associated Protein 1 business.industry lcsh:R Ubiquitination Cell cycle medicine.disease Cullin Proteins KEAP1 Immunohistochemistry 3. Good health Disease Models Animal 030104 developmental biology medicine.anatomical_structure Knockout mouse Cancer research Tubulointerstitial fibrosis lcsh:Q Kidney Diseases business 030217 neurology & neurosurgery Biomarkers Gene Deletion Kidney disease DNA Damage Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, 9:4596. Nature Publishing Group Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Cullin 3 (CUL3) is part of the ubiquitin proteasomal system and controls several cellular processes critical for normal organ function including the cell cycle, and Keap1/Nrf2 signaling. Kidney tubule-specific Cul3 disruption causes tubulointerstitial fibrosis, but little is known about the mechanisms. Therefore, we tested the hypothesis that dysregulation of the cell cycle and Keap1/Nrf2 pathway play a role in initiating the kidney injury upon Cul3 disruption. Cul3 deletion increased expression of cyclin E and p21, associated with uncontrolled proliferation, DNA damage, and apoptosis, all of which preceded proximal tubule injury. The cdk2-cyclin E inhibitor roscovitine did not prevent the effects of Cul3 deletion, but instead exacerbated the kidney injury. Injury occurred despite accumulation and activation of CUL3 substrate Keap1/Nrf2, proposed to be protective in kidney injury. Cul3 disruption led to progressive interstitial inflammation, functionally relevant renal fibrosis and death. Finally, we observed reduced CUL3 expression in several AKI and CKD mouse models and in fibrotic human kidney tissue. These data establish CUL3 knockout mice as a novel genetic CKD model in which dysregulation of the cell cycle may play a primary role in initiating tubule injury, and that CUL3 dysregulation could contribute to acute and fibrotic kidney disease. |
| Databáze: | OpenAIRE |
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