Abstract: SA-OR54
Capillaries Are Primary Targets in CKD and Tie2 Signaling Plays a Central Role in Disease Progression
Session Information
- CKD: Cutting Edge of Mechanisms
November 06, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Pietilä, Riikka Susanna, Uppsala Universitet, Uppsala, Sweden
- Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Betsholtz, Christer, Karolinska Institutet, Stockholm, Sweden
- Jeansson, Marie, Karolinska Institutet, Stockholm, Sweden
Background
Progressive renal diseases are associated with loss of peritubular capillaries, capillary rarefaction, but the underlying mechanisms are not well described. In both mouse models and patients, a decline in endothelial tyrosine kinase receptor (Tie2) signaling can be seen in CKD. We hypothesized that renal blood vessels through loss of Tie2 signaling upregulates Pdgfb that in turn act as a mitogen to activate pericytes and fibroblasts.
Methods
To investigate this, we utilized floxed alleles for Tie2 and Pdgfb together with inducible endothelial specific Cre and lineage reporter. Additional lines (Pdgfra-H2b-GFP and Pdgfrb-GFP), were crossed into the line, resulting in reporters of myofibroblasts. Mice were subjected to an experimental model of CKD, the unilateral ureter obstruction model. Capillary density and fibrosis were evaluated at 1, 3, and 10 days after obstruction. A subset of mice was treated with an Tie2 activating antibody and evaluated the same way.
Results
Our studies show that loss of Tie2 results in increased injury to peritubular capillaries and increased tubulointerstitial fibrosis in an experimental model of CKD. Tie2 ecKO mice showed reduced capillary density, reduced fenestrations, and reduced vessel perfusion. Furthermore, treatment with an Tie2 activating antibody reduced both fibrosis and loss of capillaries if started at the time of injury, while endothelial specific knockout of Pdgfb only reduced fibrosis.
Conclusion
Our results suggest that capillaries are primary targets in CKD and that Tie2 regulation affects both capillary density and tubulointesrstitial fibrosis. Tie2 activating agents should be explored as therapies for patients with chronic kidney disease.
Funding
- Private Foundation Support