title: The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury.
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.
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan No. 2 Road, Guangzhou 510080, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.forename: Alexis
authors.initials: A
authors.lastname: Sloan
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.forename: Shuangxin
authors.initials: S
authors.lastname: Liu
authors.forename: Wenjian
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009392:Nephrectomy; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D039661:Integrin beta3; D050778:NFATC Transcription Factors; D055293:Receptors, Urokinase Plasminogen Activator; D019703:Calcineurin