Modeling oxidative injury response in human kidney organoids.

Autor: Przepiorski A; Department of Developmental Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Vanichapol T; Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand., Espiritu EB; Department of Developmental Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Crunk AE; Department of Developmental Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Parasky E; Department of Developmental Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., McDaniels MD; Department of Developmental Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Emlet DR; Center for Critical Care Nephrology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Salisbury R; Department of Psychiatry, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Happ CL; Department of Psychiatry, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Vernetti LA; Department of Computational and Systems Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., MacDonald ML; Department of Psychiatry, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Kellum JA; Center for Critical Care Nephrology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Kleyman TR; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Baty CJ; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA., Davidson AJ; Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand., Hukriede NA; Department of Developmental Biology, University of Pittsburgh, School of Medicine, 3501 5th Ave., 5061 BST3, Pittsburgh, PA, 15213, USA. hukriede@pitt.edu.
Jazyk: angličtina
Zdroj: Stem cell research & therapy [Stem Cell Res Ther] 2022 Feb 21; Vol. 13 (1), pp. 76. Date of Electronic Publication: 2022 Feb 21.
DOI: 10.1186/s13287-022-02752-z
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje