Hypoxic injury triggers maladaptive repair in human kidney organoids

ABSTRACT: Reduction in blood supply to the kidneys occurs to certain extent during kidney injury (AKI). Individuals who suffered AKI are at risk of developing chronic kidney disease (CKD) through a maladaptive repair process. At present, no therapies exist to prevent the AKI to CKD transition. Here, we present a human kidney organoid model of AKI and maladaptive regeneration. Organoids were generated from human induced pluripotent stem cells and cultured in hypoxic or normoxic conditions from days 18-20 of differentiation. Organoids were collected at day 20 to assess hypoxic injury, and after a 5-day recovery in normoxic conditions to assess maladaptive repair. The transcriptome, proteome and metabolome were profiled. Gene expression analysis of day 20 hypoxic organoids identified signatures of injury, cell death (necroptosis and ferroptosis), cell cycle arrest and changes in metabolism. The maladaptive repair phenotype was supported by enrichment of pathways associated with inflammatory signals, oxidative stress, and tissue remodelling. Specific genes associated with kidney injury and disease such as GDF15, MMP7, ICAM1, TGFB1, CCN1, C3 and S100A8/9 were upregulated. Single-cell RNA sequencing localised expression of maladaptive repair genes and activation of TNF and JAK-STAT signalling pathways specific to tubular epithelial cells. Dysregulation in metabolic pathways such as glycolysis and gluconeogenesis, amino acid and lipid metabolisms were conserved in this model. Therefore, these results support the use of kidney organoids as a model of AKI and early CKD that can be used for biomarker validation, elucidation of pathological mechanisms, and drug screening.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Joel Steele  

LAB HEAD: Ana B Nunez-Nescolarde

PROVIDER: PXD042882 | Pride | 2026-06-26

REPOSITORIES: Pride