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Kidney Week

Abstract: SA-OR075

Capillaries Are Primary Targets in CKD and Loss of Tie2 Signaling Increases Vascular Injury

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Jeansson, Marie, Karolinska Institutet, Huddinge, Sweden
  • Betsholtz, Christer, Uppsala University, Uppsala, Sweden
Background

Progressive renal diseases are associated with capillary rarefaction of peritubular capillaries, but the functional alterations and 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. Here, we investigate the role of Tie2 signaling on capillary function and fibrosis in models of CKD.

Methods

Tie2 floxed mice were crossed with tamoxifen inducible endothelial specific Cadh5-Cre and a reporter line expressing TdTomato upon Cre-activation (Tie2 ECKO). This line enables both an endothelial specific KO of Tie2 and an endothelial lineage tracer. Mice were induced at 4 weeks of age to avoid developmental effects from the knockout. To study the role of Tie2 signaling in progressive renal disease we utilized the unilateral ureter obstruction (UUO) model. Additional lines (Pdgfra-H2b-GFP, Pdgfrb-GFP) were crossed into the line, resulting in reporters of myofibroblasts.

Results

Endothelial injury started already 1 day after UUO and was significantly worse in Tie2 ECKO mice compared to WT mice, including reduced capillary density, capillary fenestrations and vessel perfusion, increase tubular vacuolization and hypoxia. Blood pressure was not different between WT and Tie2 ECKO mice. Later than the endothelial injury was tubulointerstitial fibrosis starting 3 days after UUO. Fibrosis could be seen 3 and 10 days after UUO with significantly more fibrosis in Tie2 ECKO mice at each time point. Although capillary markers decreased and capillary morphology changed, the number of endothelial nuclei, as measured by the lineage tracer TdTomato, did not change. To investigate if the endothelial lineage had undergone endothelial-mesenchymal transition we utilized a myofibroblast reporter, Pdgfra-GFP, to investigate if GFP and TdTomato would colocalize after UUO. Investigation 3 and 10 days after UUO show no colocalization with TdTomato lineage although the up to 3-fold increase in total number of Pdgfra-GFP cells reflect the onset of fibrosis. Ongoing studies are analyzing single cell transcriptomes from the endothelial lineage in the above experiments.

Conclusion

Our results suggest that blood vessel function is central in progressive renal disease and that Tie2 signaling affects blood vessel function and that pro-Tie2 signaling could be an interesting therapy.

Funding

  • Private Foundation Support