Abstract
Ferroptosis, a novel type of programmed cell death, is involved in inflammation and oxidation of various human diseases, including diabetic kidney disease. The present study explored the role of high-mobility group box-1 (HMGB1) on the regulation of ferroptosis in mesangial cells in response to high glucose. Compared with healthy control, levels of serum ferritin, lactate dehydrogenase (LDH), reactive oxygen species (ROS), malonaldehyde (MDA), and HMGB1 were significantly elevated in diabetic nephropathy (DN) patients, accompanied with deregulated ferroptosis-related molecules, including long-chain acyl-CoA synthetase 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), NADPH oxidase 1 (NOX1), and glutathione peroxidase 4 (GPX4). In vitro assay revealed that erastin and high glucose both induced ferroptosis in mesangial cells. Suppression of HMGB1 restored cellular proliferation, prevented ROS and LDH generation, decreased ACSL4, PTGS2, and NOX1, and increased GPX4 levels in mesangial cells. Furthermore, nuclear factor E2-related factor 2 (Nrf2) was decreased in DN patients and high glucose-mediated translocation of HMGB1 in mesangial cells. Knockdown of HMGB1 suppressed high glucose-induced activation of TLR4/NF-κB axis and promoted Nrf2 expression as well as its downstream targets including HO-1, NQO-1, GCLC, and GCLM. Collectively, these findings suggest that HMGB1 regulates glucose-induced ferroptosis via Nrf2 pathway in mesangial cells.
Highlights
Diabetic kidney disease is one of the most common complications of diabetes characterized by macroalbuminuria, hypertension, and decreased glomerular filtration rate (GFR) [1]
In the present study, elevated levels of high-mobility group box-1 (HMGB1) were observed in diabetic nephropathy (DN) patients accompanied with deregulated ferroptosis-associated markers
Our results identified a regulatory role of HMGB1 in ferroptosis of mesangial cells, suggesting a novel therapeutic target for DN
Summary
Diabetic kidney disease is one of the most common complications of diabetes characterized by macroalbuminuria, hypertension, and decreased glomerular filtration rate (GFR) [1]. It leads the cause of end-stage renal disease (ESRD) in developed countries and accounts for approximately 16.4% of ESRD cases in China, and accounts for a significant increase in morbidity and mortality in patients with diabetes [2]. Programmed cell death is regulated by an intricate mechanism that is closely related to inflammatory processes triggered by innate immune responses. Ferroptosis, a novel type of programmed cell death, has been proved to be involved in inflammation and oxidation of various human diseases [3]. Ferroptosis is implicated in human diseases, its precise regulatory mechanism and biological functions remain elusive
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