BACKGROUND Gdf15 encodes a TGF-β superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI. METHODS We used genome editing to generate a Gdf15 nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization and genetic modification of Gdf15-expressing cells. We extensively mapped Gdf15 expression in the normal kidney and following bilateral ischemia-reperfusion injury, and quantified and compared renal responses to ischemia-reperfusion injury in the presence and absence of GDF15. In addition, we analyzed single nucleotide polymorphism association data for GDF15 for associations with patient kidney transplant outcomes. RESULTS Gdf15 is normally expressed within aquaporin 1-positive cells of the S3 segment of the proximal tubule, aquaporin 1-negative cells of the thin descending limb of the loop of Henle, and principal cells of the collecting system. Gdf15 is rapidly upregulated within a few hours of bilateral ischemia-reperfusion injury at these sites and new sites of proximal tubule injury. Deficiency of Gdf15 exacerbated acute tubular injury and enhanced inflammatory responses. Analysis of clinical transplantation data linked low circulating levels of GDF15 to an increased incidence of biopsy-proven acute rejection. CONCLUSIONS Gdf15 contributes to an early acting, renoprotective injury response, modifying immune cell actions. The data support further investigation in clinical model systems of the potential benefit from GDF15 administration in situations in which some level of tubular injury is inevitable, such as following a kidney transplant.

中文翻译：

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缺血-再灌注损伤引起的AKI后GDF15的肾脏保护和免疫调节作用。

背景技术Gdf15编码TGF-β超家族成员，其响应包括肾脏在内的多个器官系统中的应激而被迅速激活。但是，缺乏有关Gdf15活性及其对正常肾脏和AKI的影响的信息。方法我们使用基因组编辑来生成Gdf15 nuGFP-CE小鼠品系，在目标等位基因上去除Gdf15，并实现表达Gdf15的细胞的直接可视化和基因修饰。我们广泛绘制了正常肾脏和双侧缺血再灌注损伤后Gdf15表达的图谱，并量化和比较了存在和不存在GDF15时肾脏对缺血再灌注损伤的反应。此外，我们分析了GDF15的单核苷酸多态性关联数据与患者肾脏移植结局的关联。结果Gdf15通常在近端小管S3节的水通道蛋白1阳性细胞，亨利loop环的细下肢的水通道蛋白1阴性细胞和收集系统的主要细胞中表达。在这些部位和近端小管损伤的新部位，双侧缺血再灌注损伤后数小时内，Gdf15迅速上调。Gdf15的缺乏加剧了急性肾小管损伤并增强了炎症反应。对临床移植数据的分析将GDF15的低循环水平与经活检证实的急性排斥反应的发生率增加联系起来。结论Gdf15有助于早期起作用的肾保护性损伤反应，改变免疫细胞的作用。