Modeling Oxidative Injury Response in Human Kidney Organoids

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2022 Feb 22

PMID 35189973

Authors

Aneta Przepiorski

Thitinee Vanichapol

Eugenel B Espiritu

Amanda E Crunk

Emily Parasky

Michael D McDaniels

Dave R Emlet

Ryan Salisbury

Cassandra L Happ

Lawrence A Vernetti

Matthew L MacDonald

John A Kellum

Thomas R Kleyman

Catherine J Baty

Alan J Davidson

Neil A Hukriede

Affiliations

Soon will be listed here.

Abstract

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.

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