#2114 TIE2 activation promotes vascular protection of tubules to reduce PDGFB driven tubulointerstitial fibrosis in experimental chronic kidney disease

Abstract

Abstract Background and Aims The relevance of endothelial dysfunction for tubulointerstitial fibrosis in chronic kidney disease (CKD) is poorly understood. Here, we utilize gain- and loss-of-function experiments to investigate the role of endothelial tyrosine kinase TIE2 for vascular-mediated protection in experimental CKD. Method TIE2 activation was achieved using a human TIE2-activating antibody (ABX), or conditional endothelial knockout of vascular endothelial protein tyrosine phosphatase (Veptp). Conditional endothelial knockout of Tie2 served as a TIE2-incompetent signalling model. CKD was induced by unilateral ureter obstruction (UUO). Results ABX treated and Veptp knockout mice were significantly protected from UUO-induced endothelial dysfunction, tubular injury, and tubulointerstitial fibrosis. Capillary density was preserved as well as fenestrations of peritubular capillaries. In contrast, Tie2 knockout mice had aggravated disease. Mechanistically, the link between endothelial dysfunction and tubulointerstitial fibrosis was tubular expression of PDGFB, which was reduced by ABX treatment and Veptp knockout. A role for endothelial-to-mesenchymal transition was ruled out by careful lineage tracing of endothelial cells and reporter for mesenchymal cells. UUO-induced tubulointerstitial fibrosis was reduced in Pdgfb knockout mice, supporting causality of PDGFB in mesenchymal activation and fibrosis. ABX treated and Veptp knockout mice had significantly lower UUO-induced PDGFB levels. Conclusion Our data supports a key role of the endothelium and TIE2 signalling in CKD. We introduce ABX as a new therapeutic approach in CKD and demonstrate the sequence of events from endothelial dysfunction to tubulointerstitial fibrosis.