Energy depletion by cell proliferation sensitizes the kidney epithelial cells to injury.
Energy depletion by cell proliferation sensitizes the kidney epithelial cells to injury.
复制标题
细胞增殖造成的能量消耗使肾上皮细胞对损伤敏感。
DOI：
10.1152/ajprenal.00023.2023
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Bonventre,JosephV
中科院分区：
文献类型：
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作者：
Galichon,Pierre;Lannoy,Morgane;Li,Li;Serre,Justine;Vandermeersch,Sophie;Legouis,David;Valerius,MTodd;Hadchouel,Juliette;Bonventre,JosephV
急性肾损伤同时激活增殖和抗增殖通路，其后果尚未完全阐明。如果肾上皮细胞的初始增殖是成功修复所必需的，那么增殖标记物的持续存在与慢性肾脏疾病的发生有关。我们假设应激条件下的增殖会影响细胞存活率和肾脏预后。我们发现，肾脏细胞在各种应激状态下的增殖与细胞死亡有关。在体外，ATP/ADP比率在细胞周期中可重复振荡，细胞增殖与细胞内ATP/ADP比率降低有关。在体内，来自移植肾脏的转录数据显示，增殖与氧化磷酸化途径的线粒体编码基因的表达减少密切相关，而与核编码的基因无关。这些观察表明，线粒体功能是损伤后增殖的肾脏细胞产生能量的限制因素。细胞增殖增加和线粒体功能降低确实与肾脏预后不良有关。总之，增殖是一个耗能的过程，损害了细胞应对损伤的能力，强调了增殖修复和代谢恢复是成功修复肾脏不可或缺的和相互依赖的特征。细胞增殖有助于肾脏修复。我们发现，在细胞周期中，ATP水平变化，并且在体外，增殖使肾上皮细胞对叠加损伤敏感。线粒体更多的增殖和更少的能量产生与受损的肾移植的不良后果有关。这表明控制肾脏修复的时机可能有利于减轻急性肾损伤的程度。
Acute kidney injury activates both proliferative and antiproliferative pathways, the consequences of which are not fully elucidated. If an initial proliferation of the renal epithelium is necessary for the successful repair, the persistence of proliferation markers is associated with the occurrence of chronic kidney disease. We hypothesized that proliferation in stress conditions impacts cell viability and renal outcomes. We found that proliferation is associated with cell death after various stresses in kidney cells. In vitro, the ATP/ADP ratio oscillates reproducibly throughout the cell cycle, and cell proliferation is associated with a decreased intracellular ATP/ADP ratio. In vivo, transcriptomic data from transplanted kidneys revealed that proliferation was strongly associated with a decrease in the expression of the mitochondria-encoded genes of the oxidative phosphorylation pathway, but not of the nucleus-encoded ones. These observations suggest that mitochondrial function is a limiting factor for energy production in proliferative kidney cells after injury. The association of increased proliferation and decreased mitochondrial function was indeed associated with poor renal outcomes. In summary, proliferation is an energy-demanding process impairing the cellular ability to cope with an injury, highlighting proliferative repair and metabolic recovery as indispensable and interdependent features for successful kidney repair.NEW & NOTEWORTHYATP depletion is a hallmark of acute kidney injury. Proliferation is instrumental to kidney repair. We show that ATP levels vary during the cell cycle and that proliferation sensitizes renal epithelial cells to superimposed injuries in vitro. More proliferation and less energy production by the mitochondria are associated with adverse outcomes in injured kidney allografts. This suggests that controlling the timing of kidney repair might be beneficial to mitigate the extent of acute kidney injury.