Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury

Abstract

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.

CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study

“…All these features impact on the individual inflammatory and immune response and represent a dramatic bias, that must be taken into due account to extract the results that can allow to identify priorities in clinical decision. Consequently, standard statistical approaches are often not sufficient to control for the highly correlated structure between covariates and to account for the many potential confounding factors (Esposito 2020 ; Cippa, et al 2021 ).…”

Multi-phenotype genome-wide association studies of the Norfolk Island isolate implicate pleiotropic loci involved in chronic kidney disease

“…In our study, the associated SNPs were located in the region corresponding to the promoter of the transcript KCNIP4-IeΔII , hence the associated variants may have a regulatory role in gene expression. In a recent publication, Gerhardt et al 27 found that KCNIP4 was markedly up-regulated at the late injury stage in proximal tubule cells in an ischemia–reperfusion injury model for studying acute kidney injury (AKI). Kidney proximal tubule is particularly vulnerable to injury and maladaptive repair of injured tubules after AKI can lead to CKD 28 , 29 .…”

Therapies Targeting Epigenetic Alterations in Acute Kidney Injury-to-Chronic Kidney Disease Transition

“…Recent studies examined the time-course of comprehensive gene expression associated with AKI-to-CKD transition, including single-cell analyses [35][36][37][38][39]. Liu et al conducted a comprehensive gene expression analysis at multiple time points by bulk RNA-sequencing (RNA-seq) of whole kidney using a murine bilateral ischemia/reperfusion injury (IRI) model.…”