NFATc1 Identifies a Population of Proximal Tubule Cell Progenitors
NFATc1 Identifies a Population of Proximal Tubule Cell Progenitors
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DOI：
10.1681/asn.2008010094
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发表时间：
2009-02-01
影响因子：
13.6
通讯作者：
Baldwin, H. Scott
中科院分区：
文献类型：
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作者：
Langworthy, Melissa;Zhou, Bin;Baldwin, H. Scott
急性肾损伤的恢复需要肾小管细胞的再生。由于钙调磷酸酶诱导NFATc蛋白的核转运，其表达模式与钙调磷酸酶抑制剂损伤的肾单位片段相关，我们假设NFATc 1在损伤后修饰上皮再生中起作用。为了测试这一点，我们用氯化汞诱导Balb/c小鼠和Nfatc 1（+/-）小鼠的近端肾小管细胞（PTC）损伤; Nfatc 1（+/-）小鼠的PTC表现出凋亡增加、持续损伤和再生延迟。为了进一步减弱NFATc 1活性，我们每天注射环孢菌素A。环孢素A治疗的Nfatc 1（+/-）小鼠表现出快速和严重的损伤后，氯化汞，血清肌酐增加，细胞凋亡增加，减少PTC增殖，并增加死亡率与类似的治疗野生型小鼠相比。使用一种新的NFATc 1转基因株系，报告激活的NFATc 1增强子结构域的NFATc 1自身扩增的关键，我们证明了加重NFATc 1表达的PTC亚群后氯化汞诱导的损伤。此外，NFATc 1标记的抗凋亡PTC增殖，以修复受损的近端小管段。这些数据提供了居住的祖先PTC人口的证据，并建议在损伤的近端小管再生的NFATc 1的作用。
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.