The funding sources are: DFG German Research Foundation (332853055 to T.S.; TP17, TP25, Q2 to J.F. and M.J.M), Else Kröner-Fresenius Stiftung (2015_A197 to T.S., 2013_A200 to C.K), START by the Medical Faculty of the RWTH Aachen to T.S. (691433), American Heart Association Postdoctoral Fellowship 17POST33670206 to M.Z.F, R01DK051496 to J.D.S, R01DK098141 to J.A.M.
Tubulointerstitial fibrosis-- research, Cellular processes, Kidney fibrosis -- research
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 Cul3disruption 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. Cul3disruption 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.
Locate the Document
Saritas, T., Cuevas, C. A., Ferdaus, M. Z., Kuppe, C., Kramann, R., Moeller, M. J., ... & McCormick, J. A. (2019). Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis. Scientific reports, 9(1), 4596.