Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury

Abstract

Background Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. Methods We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1–2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. Results High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. Conclusions The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.

Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

“…( D-E ) snRNA-seq analysis of human kidney tissue from patients with severe AKI and controls (n=6-8). Analysis was performed on publicly available snRNA-seq data from Christian Hinze et al (39). ( D ) Bubble chart for top 10 enriched Hallmark pathways of upregulated DEGs in kidney ECs from patients with severe AKI compared to controls.…”

Single-cell transcriptomics: A new tool for studying diabetic kidney disease

“…This cell exhibited increased resistance to ferroptosis and proteotoxic stress driven by MYC-induced proliferative signaling ( Tourigny et al, 2022 ). SnRNA-seq results from patients with renal injury revealed that the distal convoluted tubules were enriched for novel damage-associated cellular states that drive renal injury through transcriptomic patterns related to oxidative stress, hypoxia, interferon response, and epithelial-mesenchymal transition ( Hinze et al, 2022 ).…”

Reference-free and cost-effective automated cell type annotation with GPT-4 in single-cell RNA-seq analysis

“…This manual annotation approach requires prior knowledge of canonical cell type markers in the given tissues and is often laborious and time-consuming. Although several automated cell type annotation methods have been developed [5][6][7][8][9][10][11][12][13] , manual cell type annotation using marker gene information remains widely used in scRNA-seq analysis [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] .…”