Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated β1-integrin endocytosis

Namiko Kobayashi, Toshiharu Ueno, Kumi Ohashi, Hanako Yamashita, Yukina Takahashi, Kazuo Sakamoto, Shun Manabe, Satoshi Hara, Yasutoshi Takashima, Takashi Dan, Ira Pastan, Toshio Miyata, Hidetake Kurihara, Taiji Matsusaka, Jochen Reiser, Michio Nagata

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Podocyte-endothelial cell cross-talk is paramount for maintaining the filtration barrier. The present study investigated the endothelial response to podocyte injury and its subsequent role in glomerulosclerosis using the podocyte-specific injury model of NEP25/LMB2 mice. 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 β1-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 β1-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 β1-integrin endocytosis represents a novel mechanism of glomerular injury leading to progressive podocytopenia. This aberrant cross-talk between podocytes and endothelial cells represents a feed forward injury response driving podocyte loss and progressive glomerulosclerosis.

Original languageEnglish (US)
Pages (from-to)F614-F626
JournalAmerican Journal of Physiology - Renal Physiology
Issue number6
StatePublished - Mar 15 2015
Externally publishedYes


  • Endocytosis
  • Integrin
  • Kidney
  • Pathology
  • Plasminogen activator inhibitor type 1
  • Podocyte

ASJC Scopus subject areas

  • Physiology
  • Urology


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