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Abstract: FR-PO952

Genetic and Pharmacological Activation of Endothelial Tie2 in Experimental CKD Alleviate Endothelial Injury and Reduces Tubulointerstitial Fibrosis by Decreasing Tubular PDGFB

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • Pietilä, Riikka Susanna, Uppsala Universitet, Uppsala, Sweden
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Betsholtz, Christer, Uppsala Universitet, Uppsala, Sweden
  • Jeansson, Marie, Uppsala Universitet, Uppsala, Sweden

Progressive renal diseases are associated with loss of peritubular capillaries. Both mouse models and patients show a decline of endothelial tyrosine kinase receptor (Tie2) signaling in CKD. We hypothesized that loss of Tie2 signaling in blood vessels leads to endothelial dysfunction, resulting in ischemia and tubular injury with onset of Pdgfb expression. Pdgfb is a mitogen for fibroblasts/pericytes and tubular overexpression leads to activation and ECM production. Furthermore, we investigate if Tie2 activation can alleviate kidney injury in experimental CKD with a Tie2 activating antibody or by genetic deletion of Veptp (a negative Tie2 regulator).


To investigate this, we utilized inducible endothelial specific Tie2 knockout mice with endothelial lineage reporter also crossed to Pdgfra-H2b-GFP as a myofibroblast reporter. Mice were subjected to experimental CKD, the UUO model. Capillary density and perfusion, tubulointerstitial fibrosis, and Pdgfb expression were evaluated in renal cortex 1-10 days after UUO. To reduce kidney injury by increasing Tie2 signaling, mice with endothelial Veptp deficiency and mice treated with a Tie2 activating antibody were investigated after UUO.


Endothelial loss of Tie2 in experimental CKD resulted in increased endothelial injury, loss of fenestrations, decreased perfusion, and increased tubulointerstitial fibrosis. We found no colocalization of endothelial lineage reporter and Pdgfra-H2b-GFP, hence, no evidence of endothelial-mesenchymal transition. Treatment with Tie2 activating antibody, or genetic deletion of endothelial Veptp, both reduced endothelial injury and maintained capillary density after UUO. UUO induced overexpression of Pdgfb was reduced by both Tie2 activating antibody and Veptp knockout as well as tubulointerstitial fibrosis.


Our results suggest that endothelial health is upstream of tubulointerstitial fibrosis and therapies to preserve vascular function are essential in CKD. In addition, we demonstrate that Tie2 signaling affects blood vessel function and that Tie2 activating agents should be explored as therapies for patients with CKD.


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