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.
Highlights
Diabetic nephropathy, a severe microvascular complication of diabetes, is characterized by proteinuria and a progressive decline in kidney function, leading to endstage kidney disease[1,2]
One-way ANOVA and Bonferroni post hoc tests were used for statistical analysis
We demonstrated that xCT and glutathione peroxidase 4 (GPX4) expression was significantly lower in cultured tubular epithelial cells that were exposed to transforming growth factor-β1 (TGF-β1), as well as in the kidneys of diabetic mice, resulting in low glutathione
Summary
A severe microvascular complication of diabetes, is characterized by proteinuria and a progressive decline in kidney function, leading to endstage kidney disease[1,2]. The pathological features of diabetic nephropathy include extracellular matrix (ECM) accumulation within the glomeruli and tubulointerstitium and glomerular and tubular cell death, all of which contribute to the development of kidney fibrosis and tubular atrophy[3,4,5]. Transforming growth factor-β (TGF-β) is regarded as one of the main mediators of the deleterious effects of the diabetic milieu, and is known to mediate kidney fibrosis and tubular cell death under diabetic conditions[11,12,13]. A number of previous studies have shown that caspase-3-dependent apoptosis and caspase-1-dependent pyroptosis are involved in tubular cell death in diabetic nephropathy[14,15]. Ferroptosis, iron-dependent cell death, is different from apoptosis, pyroptosis, and receptorinteracting protein kinase-dependent necroptosis[16]
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