Kidney organoids as a novel platform to evaluate heat‐stress‐induced acute kidney injury pathogenesis

Acute kidney injury (AKI) is a serious condition with significant global impact. To explore mechanisms and biomarkers of heat-stress-induced AKI, we used human kidney organoids derived from induced pluripotent stem cells via suspension culture. Organoids were exposed to 37, 39, and 41°C. At 41°C, we found the viability decreased over time, with cytoskeleton damage, impaired tubule absorption, apoptosis, and collagen deposition. Under extreme heat (41°C), elevated AKI markers KIM-1 and NGAL, along with cell cycle arrest markers TIMP-2*IGFBP7 were detected. Notably, TIMP-2*IGFBP7 appeared at 12 h post-exposure, preceding NGAL and KIM-1. Nascent and steady-state RNA analyses revealed suppressed oxidative phosphorylation and ATP metabolism, along with elevated histone expression, implicating their roles in heat-induced AKI. The data support that kidney organoids serve as a valuable model for investigating heat-induced AKI, providing insights into early injury biomarkers that are valuable for the development of treatments.