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In this study, we demonstrate that the activation of the endothelial tyrosine kinase TIE2 alleviates renal pathology in experimental CKD in mice. TIE2 activation was achieved using a human angiopoietin-2\u2013binding and TIE2-activating antibody (ABTAA) or through adult-induced endothelium-specific knockout of the vascular endothelial protein tyrosine phosphatase gene (\n                    <jats:italic>Veptp<\/jats:italic>\n                    ). Both methods markedly protected CKD mice from endothelial dysfunction, peritubular capillary loss, tubular epithelial injury, and tubulointerstitial fibrosis. Conversely, silencing TIE2 through adult-induced endothelium-specific knockout of the\n                    <jats:italic>Tie2<\/jats:italic>\n                    gene exacerbated CKD pathology. Additionally, we found that endothelial dysfunction promoted renal fibrosis not through endothelial-to-mesenchymal transition, as previously expected, but by inducing the expression of profibrotic PDGFB in tubular epithelial cells, a process that is inhibited by TIE2 activation. Our findings suggest that TIE2 activation via ABTAA warrants investigation as a therapy in human CKD, where there is a substantial unmet medical need.\n                  <\/jats:p>","DOI":"10.1172\/jci190286","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T16:00:16Z","timestamp":1757952016000},"source":"Crossref","is-referenced-by-count":11,"title":["TIE2 activation by antibody-clustered endogenous angiopoietin-2 prevents capillary loss and fibrosis in experimental kidney disease"],"prefix":"10.1172","volume":"135","author":[{"given":"Riikka","family":"Pietil\u00e4","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Marks-Hultstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 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