Abstract: FR-PO339

Endothelial Tie2 Deficiency Increases Tubulointerstitial Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis


  • Jeansson, Marie, Uppsala University, Uppsala, Sweden

Renal tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of underlying disease. It is characterized by an increase in aSMA+ fibroblasts, myofibroblasts, that produce collagen. We previously showed that loss of Angiopoietin-1 (Angpt1) in adult mice predisposes to fibrosis in wound healing, diabetic nephropathy, and the unilateral ureter obstruction (UUO) model. The tyrosine kinase receptor, Tie2, is expressed on endothelial cells and Angpt1 binding results in Tie2 signaling that is pro-survival and anti-inflammatory. Here, we test the hypothesis that loss of Tie2 signaling in endothelial cells results in capillary defects leading to an increased fibrotic response in kidney fibrosis.


Tie2 floxed mice were crossed with tamoxifen inducible endothelial specific Cadh5-Cre and a reporter line expressing TdTomato upon Cre-activation. This line enables both an endothelial specific KO of Tie2 and an endothelial lineage tracer. To study the role of Tie2 signaling in renal fibrosis we utilized the unilateral ureter obstruction (UUO) model of kidney fibrosis.


Endothelial specific KO of Tie2 resulted in an increase in fibrosis as seen by a 2-fold increased expression of SM22a and Col1a1 compared to controls 3 days after UUO. At the same time, there was a 4-fold increase in Kim1, suggesting more injury to tubular cells in Tie2 KO. Investigation of blood vessels before fibrotic onset 1 day after UUO, revealed less perfused capillary area and increased hypoxia in Tie2 KO mice. Ongoing work is designed to investigate blood vessel function in the early fibrotic process and to estimate the endothelial-mesenchymal contribution after UUO in controls and Tie2 knockout mice, utilizing the lineage tag of endothelial cells in the system.


Our results suggest that loss of Tie2 signaling destabilizes the endothelial cell and increases tubulointerstitial fibrosis. The mechanisms we are investigating are an early loss of endothelial cells due to endothelial-mesenchymal transition and/or apoptosis, resulting in less functional peritubular capillaries and more fibrosis.


  • Government Support - Non-U.S.