Modeling oxidative injury response in human kidney organoids
| Autor: | Ryan Salisbury, Cassandra L. Happ, Amanda E. Crunk, Aneta Przepiorski, Alan J. Davidson, Lawrence Vernetti, Dave R. Emlet, Thomas R. Kleyman, Eugenel B. Espiritu, Catherine J. Baty, Thitinee Vanichapol, Neil A. Hukriede, Emily Parasky, Matthew L. MacDonald, Michael D. McDaniels, John A. Kellum |
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| Rok vydání: | 2021 |
| Předmět: |
Pluripotent Stem Cells
Pathology medicine.medical_specialty urogenital system Chemistry Medicine (miscellaneous) Human kidney Cell Biology Kidney Biochemistry Genetics and Molecular Biology (miscellaneous) Organoids Oxidative Stress Organoid medicine Molecular Medicine Humans Oxidative injury Renal Insufficiency Chronic |
| Popis: | Background 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. Methods 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. Results 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. Conclusion 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. |
| Databáze: | OpenAIRE |
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