During sepsis, haemoglobin is released from damaged red blood cells and causes damage in the kidneys. This sepsis-associated acute kidney injury is a major concern for critically ill patients, having a profound effect on morbidity and mortality. Furthermore, there are presently no targeted therapies for sepsis-induced acute kidney injury.
In this issue, Woodard and colleagues developed a kidney organoid system derived from human pluripotent stem cells that mimics sepsis-induced injury via haemoglobin treatment. In this system, cell-free haemoglobin (CFH) treatment induced cytotoxicity and reactive oxygen species (ROS) production. The authors used transmission electron microscopy and immunostaining of endothelial markers to reveal a loss of endothelial cells and vascular networks in CFH-injured kidney organoids. They also found that CFH caused mitochondrial swelling and damage and mitochondrial DNA release. RNA sequencing uncovered elevated expression of an acute kidney injury biomarker, genes regulating tubule formation, genes associated with renal fibrosis and inflammatory response genes in the CFH-injured kidney organoids. The authors also used a cytokine array to find increased levels of cytokines associated with inflammation and damage in the organoids treated with CFH. The authors' comprehensive interrogation of these kidney organoids showcases this system as a faithful model of acute kidney injury.
The authors then treated the injured kidney organoids with ascorbate (vitamin C) and found that it reduced cytotoxicity and ROS production. Vitamin C treatment also reduced inflammatory cytokine production, alleviated mitochondrial damage, and maintained endothelial cell populations and vascular networking. Overall, this study provides a powerful system to investigate sepsis-induced kidney injury and highlights vitamin C as a promising treatment option.
DMM Research or Resource articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.
