Activation of NFAT Signaling in Podocytes Causes Glomerulosclerosis

Activation of NFAT Signaling in Podocytes Causes Glomerulosclerosis JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Wang, Y., Jarad, G., Tripathi, P., Pan, M., Cunningham, J., Martin, D. R., Liapis, H., Miner, J. H., Chen, F. 2010; 21 (10): 1657-1666

Abstract

Mutant forms of TRPC6 can activate NFAT-dependent transcription in vitro via calcium influx and activation of calcineurin. The same TRPC6 mutants can cause FSGS, but whether this involves an NFAT-dependent mechanism is unknown. Here, we generated mice that allow conditional induction of NFATc1. Mice with NFAT activation in nascent podocytes in utero developed proteinuria and glomerulosclerosis postnatally, resembling FSGS. NFAT activation in adult mice also caused progressive proteinuria and FSGS. Ultrastructural studies revealed podocyte foot process effacement and deposition of extracellular matrix. NFAT activation did not initially affect expression of podocin, synaptopodin, and nephrin but reduced their expression as glomerular injury progressed. In contrast, we observed upregulation of Wnt6 and Fzd9 in the mutant glomeruli before the onset of significant proteinuria, suggesting a potential role for Wnt signaling in the pathogenesis of NFAT-induced podocyte injury and FSGS. These results provide in vivo evidence for the involvement of NFAT signaling in podocytes, proteinuria, and glomerulosclerosis. Furthermore, this study suggests that NFAT activation may be a key intermediate step in the pathogenesis of mutant TRPC6-mediated FSGS and that suppression of NFAT activity may contribute to the antiproteinuric effects of calcineurin inhibitors.

View details for DOI 10.1681/ASN.2009121253

View details for Web of Science ID 000282999000013

View details for PubMedID 20651158

View details for PubMedCentralID PMC3013542