Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.
Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.
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DOI：
10.1073/pnas.2026684118
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发表时间：
2021-07-06
影响因子：
11.1
通讯作者：
McMahon AP
中科院分区：
文献类型：
--
作者：
Gerhardt LMS;Liu J;Koppitch K;Cippà PE;McMahon AP
单一的急性肾损伤事件会增加进展为慢性肾脏疾病(CKD)的风险。结合单核RNA测序和对受损近端小管细胞的遗传追踪，确定了缺血-再灌注损伤后空间动态的、不断演变的损伤反应。失败的近端小管修复导致促纤维化、促炎的VCam1+/CCl2+细胞类型持续存在，表现出衰老相关的分泌表型和显著的转录激活的NF-κB和AP-1信号通路信号，但没有G2/M细胞周期停滞的迹象。来自这项研究的见解可以为改善肾脏修复和防止CKD进展的策略提供参考。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疾病(CKD)的风险增加有关。AKI导致近端小管细胞(PTCs)功能障碍或死亡，触发一个鲜为人知的自体细胞修复程序。有缺陷的修复与CKD的长期过渡有关。在包括肾移植手术在内的各种临床环境中，我们进行了轻度到中度的缺血再灌注损伤(IRI)，以模拟反映肾脏损伤的损伤反应。在IRI后7天(“早期”)和28天(“晚期”)时间点，对基因标记的受损PTCs进行单核RNA测序，确定了损伤修复转变中的特定基因和途径活性。特别是，我们鉴定出VCam1+/CCL2+PTCs处于损伤的晚期阶段，其特点是显著激活了NF-κB-、肿瘤坏死因子-和AP-1-信号通路。这些PTCs群体表现出与衰老相关的分泌表型特征，但没有表现出G2/M细胞周期停滞，这与其他报道的肾损伤后适应性不良的PTCs不同。命运图谱实验确定了这些细胞在空间和时间上的不同起源。在损伤起始的皮质-髓质交界处，大多数Vcam1+/CCL2+PTCs来自早期复制的PTCs。相反，在皮质区域，只有Vcam1+/CCL2+PTCs的亚群可以追踪到早期修复细胞，这表明继发性PTC损伤发生在较晚的部位。总而言之，这些数据表明，即使是中度的IRI也与持久的损伤有关，这种损伤从CMB扩散到皮质区域。残留的修复失败的PTC可能是慢性疾病进展的触发因素。
A single acute kidney injury event increases the risk of progression to chronic kidney disease (CKD). Combining single-nucleus RNA sequencing with genetic tracing of injured proximal tubule cells identified a spatially dynamic, evolving injury response following ischemia–reperfusion injury. Failed proximal tubule repair leads to the persistence of a profibrotic, proinflammatory Vcam1+/Ccl2+ cell type exhibiting a senescence-associated secretory phenotype and a marked transcriptional activation of NF-κB and AP-1 pathway signatures, but no signs of G2/M cell cycle arrest. Insights from this study can inform strategies to improve renal repair and prevent CKD progression. 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 Vcam1+/Ccl2+ 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 G2/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 Vcam1+/Ccl2+ PTCs arose from early replicating PTCs. In contrast, in cortical regions, only a subset of Vcam1+/Ccl2+ 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.
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影响因子：
16.6
作者：
Ferreira-Gonzalez S;Lu WY;Raven A;Dwyer B;Man TY;O'Duibhir E;Lewis PJS;Campana L;Kendall TJ;Bird TG;Tarrats N;Acosta JC;Boulter L;Forbes SJ
通讯作者：
Forbes SJ
DOI：
10.1161/hypertensionaha.113.02476
发表时间：
2014-03
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Hao S;Bellner L;Zhao H;Ratliff BB;Darzynkiewicz Z;Vio CP;Ferreri NR
通讯作者：
Ferreri NR
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
41.5
作者：
Ferenbach, David A.;Bonventre, Joseph V.
通讯作者：
Bonventre, Joseph V.
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay