The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury

Bin Zhang, Wei Shi, Juan Ma, Alexis Sloan, Christian Faul, Changli Wei, Jochen Reiser, Yun Yang, Shuangxin Liu, Wenjian Wang

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Circulating and podocyte-bound urokinase receptor (uPAR) is a mediator of podocyte injury, proteinuria, and focal segmental glomerulosclerosis (FSGS) allowing pathological activation of the uPAR-β3 integrin signaling axis. Clinically, calcineurin inhibitors (e.g., cyclosporine A, CsA) are known to suppress T cells, yet are also being used to reduce proteinuria in FSGS, suggesting the possibility of signal cross talk between uPAR and calcineurin. Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). Accordingly, in vivo conditional NFATc1 activation in podocytes leads to proteinuria in mice, yet the downstream targets of NFAT remain unclear. Here, we show that inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. Pathological uPAR signals in podocytes are independent of T cells and affect cell motility via activation, but not expression, changes of the β3 integrin and can be blocked by CsA, NFAT-siRNA, or the cell-permeable NFAT inhibitor (11R-VIVIT) using rodent models of glomerular disease (LPS; 5/6 nephrectomized rats). Taken together, these findings identify podocyte uPAR as a downstream target of NFAT and provide further insights into the pathogenesis of FSGS.

Original languageEnglish (US)
Pages (from-to)1407-1420
Number of pages14
JournalJournal of Molecular Medicine
Volume90
Issue number12
DOIs
StatePublished - Dec 2012

Keywords

  • β3 integrin
  • Calcineurin
  • NFAT
  • Podocyte
  • suPAR
  • uPAR

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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  • Cite this

    Zhang, B., Shi, W., Ma, J., Sloan, A., Faul, C., Wei, C., Reiser, J., Yang, Y., Liu, S., & Wang, W. (2012). The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury. Journal of Molecular Medicine, 90(12), 1407-1420. https://doi.org/10.1007/s00109-012-0960-6