Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

Abstract

BackgroundFerroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice.MethodsDb/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice.ResultsDb/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice.ConclusionsOur study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway.

Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice

“…Notably, we found that ferroptosis was increased in HFD-challenged mice subjected to LPS stimulation. To date, studies have reported that ferroptosis can be activated in diabetes [28] and LPS stimulation [29]. However, in the present study, we found that renal ferroptosis elicited no significant effect in HFD-challenged mice without LPS stimulation.…”

Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential

“…The role of ferroptosis in the development of DN is also supported by the finding that treatment with high glucose led to ferroptosis-specific mitochondrial changes in the HK-2 cells, whereas treatment with Fer-1 significantly rescued these changes and alleviated the renal pathological injuries in diabetic DN mice through Nrf2 pathway [74]. Treatment with Fer-1 also significantly ameliorated kidney hypertrophy and albuminuria to reduce the intracranial accumulation of lipid peroxidation in the diabetic mice by the HIF-1α/HO-1 pathway [75]. In addition, it has also been reported that HO-1 is expressed specifically in glomeruli in DN, and the induction of HO-1 prevents podocyte apoptosis [76,77].…”

Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities

“…In addition, induction of HIF-1 by EGFR can make A549 lung cancer cells resistant to another type of PCD called anoikis under the lipid raft-disrupting stress (45). Emerging evidence also supports the role of HIFs in the induction of ferroptosis (46,47). Jiang et al…”