Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
J Am Soc Nephrol. 2013 Dec;24(12):2023-33. doi: 10.1681/ASN.2013010076. Epub 2013 Aug 15.
AKI induces the renoprotective upregulation of survivin expression in kidney epithelial cells, but the underlying mechanisms have not been identified. To determine the role of survivin in renal recovery from AKI, we generated mice with renal proximal tubule-specific deletion of survivin (survivin(ptKO)). Renal survivin expression increased substantially in response to ischemia-reperfusion (I/R) injury in control littermates but remained minimal in survivin(ptKO) mice. Functional and histologic data indicated similar degrees of renal injury in survivin(ptKO) and control mice 24 hours after reperfusion, but recovery was markedly delayed in survivin(ptKO) mice. In MCT cells, a mouse renal proximal tubule cell line, ATP depletion by antimycin A treatment upregulated survivin expression through a phospho-STAT3-dependent pathway. In wild-type mice, inhibition of STAT3 kinase diminished I/R-induced upregulation of STAT3 phosphorylation and survivin expression and delayed recovery. Furthermore, I/R injury activated Notch-2 signaling, and a γ-secretase inhibitor suppressed I/R-induced Notch-2 signaling, STAT3 phosphorylation, and survivin expression and delayed recovery. In MCT cells, inhibition of γ-secretase similarly attenuated antimycin A-induced Notch-2 activation, upregulation of survivin, and phosphorylation of STAT3, but STAT3 kinase inhibition did not prevent Notch-2 activation. Therefore, these data suggest that STAT3 phosphorylation and subsequent upregulation of survivin expression mediated by Notch-2 signaling in renal proximal tubule epithelial cells aid in the functional and structural recovery of the kidney from AKI.
AKI 诱导肾上皮细胞中 survivin 表达的保护上调，但潜在机制尚未确定。为了确定 survivin 在 AKI 后肾脏恢复中的作用，我们生成了肾近端小管特异性缺失 survivin 的小鼠（survivin(ptKO)）。在对照同窝仔鼠中，缺血再灌注（I/R）损伤后肾 survivin 表达显著增加，但 survivin(ptKO) 小鼠中仍保持最低水平。功能和组织学数据表明，在 I/R 后 24 小时，survivin(ptKO) 和对照小鼠的肾损伤程度相似，但 survivin(ptKO) 小鼠的恢复明显延迟。在 MCT 细胞（一种小鼠肾近端小管细胞系）中，抗霉素 A 处理导致 ATP 耗竭，通过磷酸化 STAT3 依赖性途径上调 survivin 表达。在野生型小鼠中，STAT3 激酶抑制剂抑制 I/R 诱导的 STAT3 磷酸化和 survivin 表达上调，并延迟恢复。此外，I/R 损伤激活 Notch-2 信号通路，γ-分泌酶抑制剂抑制 I/R 诱导的 Notch-2 信号通路、STAT3 磷酸化和 survivin 表达，并延迟恢复。在 MCT 细胞中，抑制 γ-分泌酶同样减弱了 antimycin A 诱导的 Notch-2 激活、survivin 的上调和 STAT3 的磷酸化，但 STAT3 激酶抑制剂不能阻止 Notch-2 的激活。因此，这些数据表明，肾近端小管上皮细胞中 Notch-2 信号通路介导的 STAT3 磷酸化和随后的 survivin 表达上调有助于 AKI 后肾脏的功能和结构恢复。
