Origin of regenerating tubular cells after acute kidney injury
Origin of regenerating tubular cells after acute kidney injury
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DOI：
10.1073/pnas.1316177111
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发表时间：
2014-01-28
影响因子：
11.1
通讯作者：
Moeller, Marcus Johannes
中科院分区：
文献类型：
--
作者：
Berger, Katja;Bangen, Joerg-Martin;Moeller, Marcus Johannes
急性肾损伤（阿基）与高发病率和死亡率相关。最近的遗传命运作图研究表明，从阿基的恢复发生在内在肾小管细胞。这些内在细胞（所谓的“分散的肾小管细胞”）是否代表固定的祖细胞，或者恢复是否涉及任何存活的肾小管细胞，这是未解决的。在这里，我们表明，多西环素诱导的壁上皮细胞（PEC）特异性PEC-反向四环素反式激活因子（rtTA）转基因小鼠也有效地标记分散的肾小管细胞群。近端肾小管细胞标记的PEC-rtTA小鼠共表达的标记物分散的肾小管细胞（肾损伤分子1，膜联蛋白A3，src抑制的C-激酶底物，和CD 44），并表现出较高的增殖指数。PEC-rtTA小鼠在不同的肾小管损伤后标记更多的肾小管细胞，但不依赖于细胞增殖，如在肾脏的生理生长中所确定的。为了确定分散的肾小管细胞是否是固定的祖细胞，在缺血再灌注损伤之前不可逆地标记细胞（遗传细胞命运作图）。在恢复过程中，标记的肾小管细胞的频率保持不变，反对一个固定的祖细胞群体。相反，当在缺血性损伤和随后的恢复过程中诱导基因标记时，标记细胞的数量显著增加，表明分散的肾小管细胞来自任何存活的肾小管细胞。总之，分散的肾小管细胞并不代表一个固定的祖细胞群，而是一种表型，几乎任何近端肾小管细胞在损伤后都可以采用。使用PEC-rtTA小鼠了解和调节这些表型变化可能会导致阿基的更特异性治疗。
Acute kidney injury (AKI) is associated with high morbidity and mortality. Recent genetic fate mapping studies demonstrated that recovery from AKI occurs from intrinsic tubular cells. It is unresolved whether these intrinsic cells (so-called "scattered tubular cells") represent fixed progenitor cells or whether recovery involves any surviving tubular cell. Here, we show that the doxycycline-inducible parietal epithelial cell (PEC)-specific PEC-reverse-tetracycline transactivator (rtTA) transgenic mouse also efficiently labels the scattered tubular cell population. Proximal tubular cells labeled by the PEC-rtTA mouse coexpressed markers for scattered tubular cells (kidney injury molecule 1, annexin A3, src-suppressed C-kinase substrate, and CD44) and showed a higher proliferative index. The PEC-rtTA mouse labeled more tubular cells upon different tubular injuries but was independent of cellular proliferation as determined in physiological growth of the kidney. To resolve whether scattered tubular cells are fixed progenitors, cells were irreversibly labeled before ischemia reperfusion injury (genetic cell fate mapping). During recovery, the frequency of labeled tubular cells remained constant, arguing against a fixed progenitor population. In contrast, when genetic labeling was induced during ischemic injury and subsequent recovery, the number of labeled cells increased significantly, indicating that scattered tubular cells arise from any surviving tubular cell. In summary, scattered tubular cells do not represent a fixed progenitor population but rather a phenotype that can be adopted by almost any proximal tubular cell upon injury. Understanding and modulating these phenotypic changes using the PEC-rtTA mouse may lead to more specific therapies in AKI.