Characterization of ferroptosis in kidney tubular cell death under diabetic conditions
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Open Access
- 8 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (2), 1-14
- https://doi.org/10.1038/s41419-021-03452-x
Abstract
Kidney tubular cell death induced by transforming growth factor-β1 (TGF-β1) is known to contribute to diabetic nephropathy, a major complication of diabetes. Caspase-3-dependent apoptosis and caspase-1-dependent pyroptosis are also involved in tubular cell death under diabetic conditions. Recently, ferroptosis, an atypical form of iron-dependent cell death, was reported to cause kidney disease, including acute kidney injury. Ferroptosis is primed by lipid peroxide accumulation through the cystine/glutamate antiporter system Xc− (xCT) and glutathione peroxidase 4 (GPX4)-dependent mechanisms. The aim of this study was to evaluate the role of ferroptosis in diabetes-induced tubular injury. TGF-β1-stimulated proximal tubular epithelial cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. xCT and GPX4 expression, cell viability, glutathione concentration, and lipid peroxidation were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. In kidney biopsy samples from diabetic patients, xCT and GPX4 mRNA expression was decreased compared to nondiabetic samples. In TGF-β1-stimulated tubular cells, intracellular glutathione concentration was reduced and lipid peroxidation was enhanced, both of which are related to ferroptosis-related cell death. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, alleviated TGF-β1-induced ferroptosis. In diabetic mice, kidney mRNA and protein expressions of xCT and GPX4 were reduced compared to control. Kidney glutathione concentration was decreased, while lipid peroxidation was increased in these mice, and these changes were alleviated by Fer-1 treatment. Ferroptosis is involved in kidney tubular cell death under diabetic conditions. Ferroptosis inhibition could be a therapeutic option for diabetic nephropathy.Keywords
Funding Information
- National Research Foundation of Korea (2019R1A2C1002524)
This publication has 60 references indexed in Scilit:
- Iron Accumulates in Huntington’s Disease Neurons: Protection by DeferoxaminePLOS ONE, 2013
- Can We Target Tubular Damage to Prevent Renal Function Decline in Diabetes?Seminars in Nephrology, 2012
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington diseaseJCI Insight, 2011
- Albuminuria and Racial Disparities in the Risk for ESRDJournal of the American Society of Nephrology, 2011
- New paradigms in cell death in human diabetic nephropathyKidney International, 2010
- System xc− and Thioredoxin Reductase 1 Cooperatively Rescue Glutathione DeficiencyJournal of Biological Chemistry, 2010
- TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTENNature, 2009
- Apoptosis: A Review of Programmed Cell DeathToxicologic Pathology, 2007
- Role of TGF-β signaling in extracellular matrix production under high glucose conditionsKidney International, 2003