ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: TH-PO353

Tubule Specific Deletion of Cullin 3 Causes Cell Cycle Dysregulation and Kidney Fibrosis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic


  • Saritas, Turgay, Oregon Health & Science University, Portland, United States
  • Cuevas, Catherina A., Oregon Health & Science University, Portland, Oregon, United States
  • Kuppe, Christoph, University Hospital RWTH Aachen, Aachen, Germany
  • Kramann, Rafael, University Hospital RWTH Aachen, Aachen, Germany
  • Moeller, Marcus J., University Hospital RWTH Aachen, Aachen, Germany
  • Singer, Jeffrey, Portland State University, Portland, Oregon, United States
  • Floege, Jürgen, University Hospital RWTH Aachen, Aachen, Germany
  • McCormick, James A., Oregon Health & Science University, Portland, Oregon, United States

Cell cycle dysregulation is involved in the pathogenesis of acute kidney injury and kidney fibrosis, but the molecular details are still poorly understood. Cullin 3 (Cul3) is part of an E3 ubiquitin ligase which controls protein abundance by promoting proteasomal degradation. Cul3-dependent ubiquitination has emerged as a key mechanism to control various critical cellular processes including cell cycle progression.


We characterized the time-course of kidney fibrosis after tubule-specific deletion of Cul3 in adult mice (doxycyline-inducible Pax8-rtTA-LC1 system) using Western blot, immunofluorescence (IF) and immunohistochemistry (IHC). In addition, Cul3 expression was analysed in different mouse models of kidney fibrosis (unilateral ureteral obstruction (UUO), ischemia/reperfusion injury (IRI) and nephrotoxic nephritis (NTN)).


Cul3 deletion caused progressive loss of kidney function within weeks and death at around 7-8 months. At 2 weeks after induction of Cul3 deletion, mice developed progressive tubular injury and were positive for NGAL and KIM-1 staining. At the same time-point, Cul3 substrates cyclin E (+62%, p<0.05) and p21 (+474%, p<0.005) were significantly increased, but p27 was reduced (-75%, p<0.05) by Western blot analysis. This was associated with increased tubular expression of cell cycle proliferation markers (cyclin D1 (5.2-fold), Ki67 (3.9-fold), PCNA (17.6-fold)), and also the G2/M pH3 (5.8-fold), using IF and IHC. 4 weeks after induction of Cul3 deletion, PAS/H&E-stained sections revealed loss of brush borders, tubule dilation, necrotic cell cast formation, caspase-3-positive apoptosis and interstitial inflammation (e.g. CD3-positive cells (14.7-fold)). Cul3-deficient tubules were adjacent to areas of increased extracellular matrix accumulation (30% and 18% of area positive for picrosirius red and alpha-smooth muscle actin (aSMA), respectively, p<0.001). In UUO, IRI and NTN, we observed reduced tubular Cul3 expression in areas where peritubular expression of aSMA was increased.


These data suggest a critical role for Cul3 in epithelial cell cycle dysregulation, dedifferentiation and the development of kidney fibrosis. Thus, Cul3 might be a promising novel therapeutic target in AKI to CKD transition and fibrosis development.


  • Government Support - Non-U.S.