Factors that May Protect the Native Hibernator Syrian Hamster Renal Tubular Epithelial Cells from Ferroptosis Due to Warm Anoxia-Reoxygenation

Abstract

Warm anoxia-reoxygenation induces ferroptotic cell death in mouse proximal renal tubular epithelial cells (RPTECs), whereas RPTECs of the native hibernator Syrian hamster resist cell death. Clarifying how hamster cells escape ferroptosis may reveal new molecular targets for preventing or ameliorating ischemia-reperfusion-induced human diseases or expanding the survival of organ transplants. Mouse or hamster RPTECs were subjected to anoxia and subsequent reoxygenation. Cell death was assessed with the lactated dehydrogenase (LDH) release assay and lipid peroxidation by measuring cellular malondialdehyde (MDA) fluorometrically. The effect of the ferroptosis inhibitor α-tocopherol on cell survival was assessed by the 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) assay. The expression of the critical ferroptotic elements cystine-glutamate antiporter (xCT), ferritin, and glutathione peroxidase 4 (GPX4) was assessed by Western blot. Contrary to mouse RPTECs, hamster RPTECs resisted anoxia-reoxygenation-induced cell death and lipid peroxidation. In mouse RPTECs, α-tocopherol increased cell survival. Anoxia increased the levels of xCT, ferritin, and GPX4 in both cell types. During reoxygenation, at which reactive oxygen species overproduction occurs, xCT and ferritin decreased, whereas GPX4 increased in mouse RPTECs. In hamster RPTECs, reoxygenation raised xCT and ferritin, but lowered GPX4. Hamster RPTECs resist lipid peroxidation-induced cell death. From the three main evaluated components of the ferroptotic pathway, the increased expression of xCT and ferritin may contribute to the resistance of the hamster RPTECs to warm anoxia-reoxygenation.

Role of indoleamine 2,3-dioxygenase in ischemia-reperfusion injury of renal tubular epithelial cells

“…Notably, confirming the pathophysiological difference between the two phases of I-R injury, previous studies showed that during ischemia, RPTECs death ensues through apoptosis (11,12). In contrast to this, reperfusion induces lipid peroxidation and ferroptotic cell death (12)(13)(14).…”

Reoxygenation induces reactive oxygen species production and ferroptosis in renal tubular epithelial cells by activating aryl hydrocarbon receptor

“…With regards reoxygenation-induced cell death, previous studies using primary RPTECs and similar experimental conditions have demonstrated that reoxygenation leads to lipid peroxidation and ferroptotic cell death (5,6). Elegant research using isolated murine renal tubules detected the same (7).…”

“…During ischemia, cell energy collapse induces cell death, whereas during reperfusion, cell death results from increased reactive oxygen species (ROS) production ( 1 – 3 ). Regarding renal tubular epithelial cells, a study demonstrated that under anoxia, cells die through apoptosis, whereas reoxygenation induces lipid peroxidation-induced cell death, also known as ferroptosis ( 5 , 6 ). The latter has also been detected in isolated mouse renal tubules, confirming the different pathophysiology of ischemia- and reperfusion-induced cell injury ( 7 ).…”

The H2S–Nrf2–Antioxidant Proteins Axis Protects Renal Tubular Epithelial Cells of the Native Hibernator Syrian Hamster from Reoxygenation-Induced Cell Death

“…Ferroptosis or membrane lipid peroxidation-induced cell death plays an essential role in I-R ROS-mediated cell death [21]. In non-hibernating species, ferroptosis has been identified as a type of renal tubular epithelial cell death due to I-R and the cause of subsequent AKI [25][26][27][28][29]. Various other types of cell death have also been incriminated for I-R-induced AKI [30].…”