Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis.

ABSTRACT: 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 accumula

SUBMITTER: Saritas T 

PROVIDER: S-EPMC6418206 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature