Activation of NFAT signaling in podocytes causes glomerulosclerosis.
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.
Wang
Yinqiu
Y
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jarad
George
G
Tripathi
Piyush
P
Pan
Minggui
M
Cunningham
Jeanette
J
Martin
Daniel R
DR
Liapis
Helen
H
Miner
Jeffrey H
JH
Chen
Feng
F
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004318:Doxycycline; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000648:ultrastructure; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D014886:Weaning
D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D004318:Doxycycline