Renal Section, Department of Medicine, Boston University, Boston, Massachusetts 02118, USA.
Kidney Int. 2011 Jul;80(1):29-40. doi: 10.1038/ki.2011.120. Epub 2011 May 11.
Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the 'perfect storm' for outer mitochondrial membrane injury to release its cellular 'executioners'. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.
对急性肾损伤 (AKI) 中肾细胞死亡的机制的深入了解产生了新的治疗靶点。显然，急性肾小管坏死的典型病变不足以描述肾缺血、肾毒物暴露或败血症对肾小球滤过率的影响。实验证据支持细胞凋亡在 AKI 中的致病作用。有趣的是，近端肾小管上皮细胞对凋亡非常敏感，该部位的损伤导致器官衰竭。在凋亡过程中，各种精心协调的事件汇聚在线粒体，即整合由 BCL2（B 细胞淋巴瘤 2）蛋白家族产生的生死信号的细胞器。死亡需要线粒体外膜损伤的“完美风暴”来释放其细胞“执行者”。这个过程的复杂性为有效的干预措施提供了新的靶点，无论是在肾损伤之前还是之后。抑制凋亡似乎至关重要，因为受损肾脏释放的循环因子会诱导包括心脏、肺、肝和脑在内的远处器官的凋亡和炎症，这可能导致 AKI 相关的高发病率和死亡率。对线粒体损伤上游的已知应激激酶的操纵、内源性抗凋亡蛋白的诱导以及对肾细胞凋亡的时机和后果的更好理解，将不可避免地改善人类 AKI 的预后。
