期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2026684118
关键词
acute kidney injury; proximal tubule; repair; transcriptomics; single-nucleus RNA sequencing
资金
- German Research Foundation [GE 3179/1-1]
- Swiss National Science Foundation [167773]
- Gianella Foundation
- Balli Foundation
- ReBuilding The Kidney Partnership grant from National Institute of Diabetes and Digestive and Kidney Diseases [U01DK107350]
- ReBuilding The Kidney Program grant [UC2DK126024]
The study found that even mild to moderate ischemia-reperfusion injury can cause lasting damage, spreading from the cortico-medullary boundary (CMB) to cortical regions, and the remaining failed-repair PTCs may be triggers for chronic disease 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 Vcam7(+)/ Ccl2(+) PTCs at a late injury stage distinguished by marked activation of NF-KB-, TNF-, and AP-1-signaling pathways. This population of PTCs showed features of a senescence-associated secretory phenotype but did not exhibit G(2)/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 Vcam7(+)/Ccl(2+) PTCs arose from early replicating PTCs. In contrast, in cortical regions, only a subset of Vcam7(+)/ Ccl(2+) PTCs could be traced to early repairing cells, suggesting latearising 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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