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.
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Acknowledgments
This work was supported by grants from the Guangdong Science & Technology Department and in part by grants from the National Institute of Health (DK073495 and DK089394 to Dr. Reiser). We thank Dr. P Mundel (Massachusetts General Hospital, Boston, USA) for providing conditionally immortalized mouse podocytes.
Disclosures
Jochen Reiser and Changli Wei are inventors on pending and issued patents on the development of novel therapeutics for proteinuric kidney diseases. They stand to gain royalties from their commercialization.
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Bin Zhang, Juan Ma, and Yun Yang contributed equally to this work.
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Zhang, B., Shi, W., Ma, J. et al. The calcineurin–NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury. J Mol Med 90, 1407–1420 (2012). https://doi.org/10.1007/s00109-012-0960-6
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DOI: https://doi.org/10.1007/s00109-012-0960-6