To investigate Th17 cells in the setting of acute kidney injury (AKI), the master regulator of Th17 cell differentiation, RORγT, was mutated in Lewis rats using CRISPR/Cas9 technology. In response to 40 min bilateral renal I/R, Rorc^-/- rats were resistant to injury relative to wild-type Rorc^+/+ rats. This protection was associated with inhibition of IL17 expression and reduced infiltration of CD4+ cells, CD8+ cells, B-cells and macrophages. To evaluate the effect of Th17 cells on repair, ischemia was increased to 50 min in Rorc^-/- rats. This maneuver equalized the initial level of injury in Rorc^-/- and Rorc^+/+ rats 1 to 2 days post I/R based on serum creatinine values. However Rorc^-/- rats, but not Rorc^+/+ rats, failed to successfully recover renal function and had high mortality by 4 days post I/R. Kidney tubules from Rorc^+/+ rats showed evidence of repair by day-4 post I/R, while Rorc^-/- rats showed persistent necrosis and elevated cell proliferation. Adoptive transfer of CD4+ cells from spleen of Rorc^+/+ rats or supplementation of exogenous rIL17 by osmotic mini-pump improved renal function and survival of Rorc^-/- rats following 50 min of I/R. This was associated with a relative decrease in the number of M1-type macrophages and a relative increase in the percentage of T-regulatory cells. Taken together, these data suggest Th17 cells have both a deleterious and beneficial role in kidney injury and recovery, contributing to early post-ischemic injury and inflammation but may also be critical in resolution of inflammation during kidney repair.

中文翻译：

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RORγT 的突变揭示了 Th17 细胞在肾缺血再灌注损伤的损伤和恢复中的作用。

为了研究急性肾损伤 (AKI) 环境中的 Th17 细胞，使用 CRISPR/Cas9 技术在 Lewis 大鼠中突变了 Th17 细胞分化的主要调节因子 RORγT。响应 40 分钟双侧肾 I/R，Rorc ^-/-大鼠相对于野生型 Rorc ^+/+大鼠对损伤具有抵抗力。这种保护作用与抑制 IL17 表达和减少 CD4+ 细胞、CD8+ 细胞、B 细胞和巨噬细胞浸润有关。为了评估 Th17 细胞对修复的影响，将 Rorc ^-/-大鼠的缺血时间增加到 50 分钟。根据血清肌酐值，该操作在 I/R 后 1 至 2 天平衡了 Rorc ^-/-和 Rorc ^+/+大鼠的初始损伤水平。然而罗克^-/-大鼠，但不是 Rorc ^+/+大鼠，未能成功恢复肾功能，并且在 I/R 后 4 天具有高死亡率。Rorc ^+/+大鼠的肾小管在I/R 后第 4 天显示出修复迹象，而 Rorc ^-/-大鼠显示出持续性坏死和细胞增殖升高。从 Rorc ^+/+大鼠脾脏中过继转移 CD4+ 细胞或通过微型渗透泵补充外源性 rIL17 改善了 Rorc ^{-/- 的}肾功能和存活率I/R 50 分钟后的大鼠。这与 M1 型巨噬细胞数量的相对减少和 T 调节细胞百分比的相对增加有关。总之，这些数据表明 Th17 细胞在肾损伤和恢复中具有有害和有益作用，有助于早期缺血后损伤和炎症，但也可能对肾脏修复过程中炎症的消退至关重要。