Department of Anesthesiology, College of Physicians and Surgeons of Columbia University , New York, New York.
Department of Pathology, College of Physicians and Surgeons of Columbia University , New York, New York.
Am J Physiol Renal Physiol. 2018 May 1;314(5):F809-F819. doi: 10.1152/ajprenal.00569.2017. Epub 2018 Jan 3.
We previously demonstrated that kidney peptidylarginine deiminase-4 (PAD4) plays a critical role in ischemic acute kidney injury (AKI) in mice by promoting renal tubular inflammation and neutrophil infiltration (Ham A, Rabadi M, Kim M, Brown KM, Ma Z, D'Agati V, Lee HT. Am J Physiol Renal Physiol 307: F1052-F1062, 2014). Although the role of PAD4 in granulocytes including neutrophils is well known, we surprisingly observed profound renal proximal tubular PAD4 induction after renal ischemia-reperfusion (I/R) injury. Here we tested the hypothesis that renal proximal tubular PAD4 rather than myeloid-cell lineage PAD4 plays a critical role in exacerbating ischemic AKI by utilizing mice lacking PAD4 in renal proximal tubules (PAD4 PEPCK Cre mice) or in granulocytes (PAD4 LysM Cre mice). Mice lacking renal proximal tubular PAD4 were significantly protected against ischemic AKI compared with wild-type (PAD4) mice. Surprisingly, mice lacking PAD4 in myeloid cells were also protected against renal I/R injury although this protection was less compared with renal proximal tubular PAD4-deficient mice. Renal proximal tubular PAD4-deficient mice had profoundly reduced renal tubular apoptosis, whereas myeloid-cell PAD4-deficient mice showed markedly reduced renal neutrophil infiltration. Taken together, our studies suggest that both renal proximal tubular PAD4 as well as myeloid-cell lineage PAD4 play a critical role in exacerbating ischemic AKI. Renal proximal tubular PAD4 appears to contribute to ischemic AKI by promoting renal tubular apoptosis, whereas myeloid-cell PAD4 is preferentially involved in promoting neutrophil infiltration to the kidney and inflammation after renal I/R.
我们之前的研究表明，肾肽酰精氨酸脱亚氨酶 4（PAD4）通过促进肾小管炎症和中性粒细胞浸润在小鼠缺血性急性肾损伤（AKI）中发挥关键作用（Ham A、Rabadi M、Kim M、Brown KM、Ma Z、D'Agati V、Lee HT。Am J Physiol Renal Physiol 307：F1052-F1062，2014）。尽管 PAD4 在包括中性粒细胞在内的粒细胞中的作用是众所周知的，但我们出人意料地观察到肾缺血再灌注（I/R）损伤后肾近端小管 PAD4 的明显诱导。在这里，我们利用缺乏肾近端小管 PAD4（PAD4 PEPCK Cre 小鼠）或粒细胞 PAD4（PAD4 LysM Cre 小鼠）的小鼠来测试以下假设：肾近端小管 PAD4 而不是髓系细胞系 PAD4 通过加剧缺血性 AKI 发挥关键作用。与野生型（PAD4）小鼠相比，缺乏肾近端小管 PAD4 的小鼠对缺血性 AKI 的保护作用明显增强。令人惊讶的是，缺乏髓系细胞 PAD4 的小鼠也对肾 I/R 损伤有保护作用，尽管这种保护作用不如肾近端小管 PAD4 缺陷小鼠明显。肾近端小管 PAD4 缺陷小鼠的肾小管凋亡明显减少，而髓系细胞 PAD4 缺陷小鼠的肾中性粒细胞浸润明显减少。总之，我们的研究表明，肾近端小管 PAD4 和髓系细胞谱系 PAD4 均在加剧缺血性 AKI 中发挥关键作用。肾近端小管 PAD4 似乎通过促进肾小管凋亡导致缺血性 AKI，而髓系细胞 PAD4 主要参与肾 I/R 后促进中性粒细胞浸润和炎症。
