Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033.
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033
Proc Natl Acad Sci U S A. 2021 Jul 6;118(27). doi: 10.1073/pnas.2026684118.
Acute kidney injury (AKI), commonly caused by ischemia, sepsis, or nephrotoxic insult, is associated with increased mortality and a heightened risk of chronic kidney disease (CKD). AKI results in the dysfunction or death of proximal tubule cells (PTCs), triggering a poorly understood autologous cellular repair program. Defective repair associates with a long-term transition to CKD. We performed a mild-to-moderate ischemia-reperfusion injury (IRI) to model injury responses reflective of kidney injury in a variety of clinical settings, including kidney transplant surgery. Single-nucleus RNA sequencing of genetically labeled injured PTCs at 7-d ("early") and 28-d ("late") time points post-IRI identified specific gene and pathway activity in the injury-repair transition. In particular, we identified / PTCs at a late injury stage distinguished by marked activation of NF-κB-, TNF-, and AP-1-signaling pathways. This population of PTCs showed features of a senescence-associated secretory phenotype but did not exhibit G/M cell cycle arrest, distinct from other reports of maladaptive PTCs following kidney injury. Fate-mapping experiments identified spatially and temporally distinct origins for these cells. At the cortico-medullary boundary (CMB), where injury initiates, the majority of / PTCs arose from early replicating PTCs. In contrast, in cortical regions, only a subset of / PTCs could be traced to early repairing cells, suggesting late-arising sites of secondary PTC injury. Together, these data indicate even moderate IRI is associated with a lasting injury, which spreads from the CMB to cortical regions. Remaining failed-repair PTCs are likely triggers for chronic disease progression.
急性肾损伤（AKI），通常由缺血、脓毒症或肾毒性损伤引起，与死亡率增加和慢性肾脏病（CKD）风险增加有关。AKI 导致近端肾小管细胞（PTC）功能障碍或死亡，触发了一种了解甚少的自体细胞修复程序。修复缺陷与长期向 CKD 的转变有关。我们进行了轻度至中度缺血再灌注损伤（IRI），以模拟各种临床情况下的肾损伤反应，包括肾移植手术。在 IRI 后 7 天（“早期”）和 28 天（“晚期”）对遗传标记的损伤 PTC 进行的单细胞 RNA 测序，确定了损伤-修复过渡中特定的基因和途径活性。特别是，我们鉴定了在晚期损伤阶段的 PTCs，其特征是 NF-κB、TNF 和 AP-1 信号通路的显著激活。这群 PTCs 表现出衰老相关分泌表型的特征，但没有表现出 G1/M 细胞周期停滞，与其他关于肾损伤后适应性不良 PTC 的报告不同。命运图谱实验确定了这些细胞的空间和时间上不同的起源。在皮质-髓质边界（CMB），损伤开始的地方，大多数 / PTCs 来自早期复制的 PTCs。相比之下，在皮质区域，只有一部分 / PTCs 可以追溯到早期修复的细胞，表明晚期出现的继发 PTC 损伤部位。总之，这些数据表明，即使是轻度的 IRI 也与持久的损伤有关，这种损伤从 CMB 扩散到皮质区域。未修复的剩余失败的 PTCs 可能是慢性疾病进展的触发因素。
