Modeling oxidative injury response in human kidney organoids

Hemolysis occurs in many injury settings and can trigger disease processes. In the kidney, extracellular hemoglobin can induce damage via several mechanisms. These include oxidative stress, mitochondrial dysfunction, and inflammation, which promote fibrosis and chronic kidney disease. Understanding...

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Published in:Stem cell research & therapy 2022-02, Vol.13 (1), p.76-76, Article 76
Main Authors: Przepiorski, Aneta, Vanichapol, Thitinee, Espiritu, Eugenel B, Crunk, Amanda E, Parasky, Emily, McDaniels, Michael D, Emlet, Dave R, Salisbury, Ryan, Happ, Cassandra L, Vernetti, Lawrence A, MacDonald, Matthew L, Kellum, John A, Kleyman, Thomas R, Baty, Catherine J, Davidson, Alan J, Hukriede, Neil A
Format: Article
Language:English
Subjects:
Analysis
Apoptosis
Chronic kidney failure
Glycosylated hemoglobin
Health aspects
Hemin
Humans
iPSCs
Kidney - metabolism
Kidney organoids
Mitochondria
Organoids - metabolism
Oxidative Stress
Pluripotent Stem Cells
Porphyrins
Renal injury
Renal Insufficiency, Chronic - metabolism
ROS
Saturated fatty acids
Scientific equipment and supplies industry
Stem cells
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Summary:Hemolysis occurs in many injury settings and can trigger disease processes. In the kidney, extracellular hemoglobin can induce damage via several mechanisms. These include oxidative stress, mitochondrial dysfunction, and inflammation, which promote fibrosis and chronic kidney disease. Understanding the pathophysiology of these injury pathways offers opportunities to develop new therapeutic strategies. To model hemolysis-induced kidney injury, human kidney organoids were treated with hemin, an iron-containing porphyrin, that generates reactive oxygen species. In addition, we developed an induced pluripotent stem cell line expressing the biosensor, CytochromeC-GFP (CytoC-GFP), which provides a real-time readout of mitochondrial morphology, health, and early apoptotic events. We found that hemin-treated kidney organoids show oxidative damage, increased expression of injury markers, impaired functionality of organic anion and cation transport and undergo fibrosis. Injury could be detected in live CytoC-GFP organoids by cytoplasmic localization of fluorescence. Finally, we show that 4-(phenylthio)butanoic acid, an HDAC inhibitor with anti-fibrotic effects in vivo, reduces hemin-induced human kidney organoid fibrosis. This work establishes a hemin-induced model of kidney organoid injury. This platform provides a new tool to study the injury and repair response pathways in human kidney tissue and will assist in the development of new therapeutics.
ISSN:1757-6512
1757-6512
DOI:10.1186/s13287-022-02752-z