NFATc1 Identifies a Population of Proximal Tubule Cell Progenitors

Recovery from acute kidney injury requires regeneration of tubule cells. Because calcineurin induces nuclear transport of NFATc proteins, whose expression pattern correlates with the nephron segments injured by calcineurin inhibitors, we hypothesized that NFATc1 plays a role in modifying epithelial regeneration after injury. To test this, we induced proximal tubular cell (PTC) injury in Balb/c mice and Nfatc1(+/-) mice with mercuric chloride; the PTCs of Nfatc1(+/-) mice demonstrated increased apoptosis, sustained injury, and delayed regeneration. To attenuate NFATc1 activity further, we injected cyclosporin A daily. Cyclosporin A-treated Nfatc1(+/-) mice demonstrated rapid and severe injury after administration of mercuric chloride, with increased serum creatinine, increased apoptosis, decreased PTC proliferation, and increased mortality compared with similarly treated wild-type mice. Using a novel NFATc1 transgenic line that reports activation of an NFATc1 enhancer domain critical for NFATc1 autoamplification, we demonstrated accentuated NFATc1 expression in a PTC subpopulation after mercuric chloride-induced injury. In addition, NFATc1-labeled, apoptosis-resistant PTCs proliferated to repair the damaged proximal tubule segment. These data provide evidence for a resident progenitor PTC population and suggest a role for NFATc1 in the regeneration of injured proximal tubules.