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NEP25\/LMB2 mice showed proteinuria and local podocyte loss accompanied by thrombotic microangiopathy on day 8. Mice showed an increase of glomerular plasminogen activator inhibitor type 1 (PAI-1) mRNA and aberrant endothelial PAI-1 protein already on day 1, before thrombosis and proteinuria. A PAI-1-specific inhibitor reduced proteinuria and thrombosis and preserved podocyte numbers in NEP25\/LMB2 mice by stabilization of \u03b2<jats:sub>1<\/jats:sub>-integrin translocation. Heparin loading significantly reduced thrombotic formation, whereas proteinuria and podocyte numbers were unchanged. Immortalized podocytes treated with PAI-1 and the urokinase plasminogen activator (uPA) complex caused significant cell detachment, whereas podocytes treated with PAI-1 or uPA alone or with the PAI-1\/uPA complex pretreated with an anti-uPA receptor (uPAR) antibody failed to cause detachment. Confocal microscopy and cell surface biotinylation experiments showed that internalized \u03b2<jats:sub>1<\/jats:sub>-integrin was found together with uPAR in endocytotic vesicles. The administration of PAI-1 inhibitor or uPAR-blocking antibody protected cultured podocytes from cell detachment. In conclusion, PAI-1\/uPA complex-mediated uPAR-dependent podocyte \u03b2<jats:sub>1<\/jats:sub>-integrin endocytosis represents a novel mechanism of glomerular injury leading to progressive podocytopenia. This aberrant cross-talk between podocytes and endothelial cells represents a feedforward injury response driving podocyte loss and progressive glomerulosclerosis.<\/jats:p>","DOI":"10.1152\/ajprenal.00616.2014","type":"journal-article","created":{"date-parts":[[2015,1,14]],"date-time":"2015-01-14T06:50:01Z","timestamp":1421218201000},"page":"F614-F626","source":"Crossref","is-referenced-by-count":47,"title":["Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated \u03b2<sub>1<\/sub>-integrin endocytosis"],"prefix":"10.1152","volume":"308","author":[{"given":"Namiko","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Department of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiharu","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Pathology, Graduate School of 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