Characterization of ferroptosis in kidney tubular cell death under diabetic conditions

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.

Ferrostatin-1 Attenuates Mechanical Hypersensitivity in Rats with Streptozotocin-Induced Diabetes by Inhibiting Spinal Ferroptosis

“…Herein, we proposed that the levels of iron and ferroptosis activity were signi cantly elevated in the spinal cord, which promoted tactile allodynia in DM rats. Similar results were obtained for other DM complications, such as diabetic nephropathy (Kim et al, 2021) and cardiomyopathy (Chen et al, 2020a), which indicated that the elevation of iron levels as well as the induction of cell ferroptosis in target organs was closely involved in the occurrence of DM complications.…”

“…Previous studies have indicated that the development of neuropathic pain secondary to peripheral nerve trauma appeared to occur alongside ferroptosis in the spinal dorsal horn neurons (Guo et al, 2021;Wang et al, 2021). Importantly, accumulating evidence has highlighted the role of iron-dependent ferroptosis in DM as well as a variety of diabetic complications, and the application of ferroptosis antagonists, including liproxstatin-1 (Lip-1) and ferrostatin-1 (Fer-1), demonstrated obvious curative effects against these hyperglycemia-induced complications (Kim et al, 2021;Li et al, 2020;Ma et al, 2020). Moreover, it was reported that a high glucose concentration results in DNP hypersensitivity, probably by disrupting the functions of cell mitochondria and subsequent generation of reactive oxygen species (ROS) (Sasson, 2017;Shokrzadeh et al, 2018).…”

Role of Ferroptosis in Lung Diseases

“… 28 GPX4 overexpression inhibits ROS production and lipid peroxidation, 29 while a decrease in GPX4 activity or expression results in the accumulation of intracellular lipid peroxide, which leads to ferroptosis. 34 Recent studies have shown that knockout of GPX4 can activate macrophages and microglia in the kidney and hippocampus, trigger an inflammatory response, and ultimately lead to organ damage. 35 Interleukin-4 (IL)-4 and IL-13 can inhibit GPX4 expression, which coincides with increased expression of arachidonic acid lipoxygenases 15 (ALOX15) in a variety of tissues, such as lung, thus permitting robust production of key inflammatory intermediates.…”

The Cross‐Link between Ferroptosis and Kidney Diseases

“…Other researchers have also found ferroptosis-specific mitochondrial changes in the HK-2 cell line induced by high glucose, while fenofibrate regulates the ferroptosis signaling pathway to alleviate tissue damage [ 143 ]. In a recent study, typical features of ferroptosis were observed in kidney biopsy specimens of patients with DN [ 144 ]. This breakthrough will improve research on ferroptosis and DN, and studies will no longer be limited to the cellular and animal levels.…”