Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy

Li, Shuangwen; Li, Zheng; Zhang, Jun; Liu, Xuejun; Wu, Zhongming

doi:10.1016/j.freeradbiomed.2020.10.323

Cited by 248 publications

(213 citation statements)

References 47 publications

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“…Fenofibrate inhibits diabetes-related iron death by upregulating the expression of Nrf2 and delays the progression of nephropathy. 78 Quercetin may have a beneficial effect on type 2 diabetic patients by inhibiting iron deposition in the pancreas and effectuating iron death of pancreatic β-cells. 79 Clinical studies have shown that serum iron metabolism indexes (iron, ferritin, and transferrin saturation) and insulin resistance index (HOMA-IR) in patients with gestational diabetes were higher than in the control group, and regression analysis indicated that serum ferritin and Tf saturation were significantly positively correlated with HOMA-IR index.…”

Section: Molecular Mechanisms Of Non-enzymatic Glycated Tf In Diabetes and Diabetic Complicationsmentioning

confidence: 99%

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Ma¹,

Cai²,

Wang³

et al. 2021

DMSO

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Diabetes is a metabolic disease characterized by high blood sugar. Its complications may damage multiple organs, such as eyes, kidneys, heart, blood vessels, and nerves, severely threatening human health. Transferrin (Tf) is a major iron transport protein in the body. Recent studies have shown that the degree of non-enzymatic glycated modification of Tf is increased in diabetic patients, and glycated Tf is closely related to the occurrence and development of diabetes and diabetic complications. However, the molecular mechanisms underlying this glycated modification in diabetes and diabetic complications are still unclear. It is speculated that the mechanism may be that glycated modification reduces the binding ability of Tf and its receptor TfR, followed by excessive iron accumulation in the body. Iron overload in the body may further lead to the death of pancreatic beta cells and insulin resistance by increasing oxidative stress, inducing iron death, interfering with the insulin signaling pathway, and causing autophagy deficiency. In addition, non-enzymatic glycation affects the binding of Tf with chromium and reduces the ability of Tf to transport chromium into tissues, resulting in a decrease in the levels of chromium in tissues and ultimately affecting the sensitivity of tissues to insulin. In diabetic patients, the concentrations of glycated Tf in serum were significantly correlated with those of fructosamine.Tf has a shorter half-life, and not affected by anemia or hypoalbuminemia and less negative charge under physiological conditions, while glycated modification could not change the isoelectric point of Tf, which easily passes through the negatively charged basement membrane of the glomerulus. Therefore, compared to glucosamine, HbA1C, etc., glycated Tf may be a future biomarker for evaluating short-term glycemic control and early renal damage in diabetic patients.

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Section: Molecular Mechanisms Of Non-enzymatic Glycated Tf In Diabetes and Diabetic Complicationsmentioning

confidence: 99%

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Ma¹,

Cai²,

Wang³

et al. 2021

DMSO

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“…HG-stimulated human renal proximal tubule (HK-2) cells were widely used as the in vitro models of DN [18][19][20]. The present study was designed to investigate the effects of hyperoside on apoptosis and inflammation of HG-treated HK-2 cells.…”

Section: Introductionmentioning

confidence: 99%

Hyperoside Protects HK-2 Cells Against High Glucose-Induced Apoptosis and Inflammation via the miR-499a-5p/NRIP1 Pathway

Zhou

Shu

Sun

et al. 2021

Pathol. Oncol. Res.

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Hyperoside, a flavonol glycoside, is derived from plants of the genera Hypericum and Crataegus. Recent studies have indicated the anti-apoptotic and anti-inflammatory roles of hyperoside. The present study was designed to measure the effects of hyperoside on high glucose (HG)-treated HK-2 cells. HK-2 is a human papillomavirus 16 transformed cell line and can be used as a model for normal tubular cell. Cell apoptosis was examined by TUNEL assays and flow cytometry analysis. Inflammatory response was detected by Enzyme linked immunosorbent assay kits. Western blotting was applied to detect protein levels of apoptosis-related genes and inflammatory cytokines. Mechanistical assays including luciferase reporter and RNA pull down assays were applied to detect the binding relationship between molecules. We identified that hyperoside protected HK-2 cells against HG-induced apoptosis and inflammation. Moreover, miR-499a-5p was upregulated by hyperoside in a dose dependent manner. MiR-499a-5p inhibition rescued the suppressive effects of hyperoside on apoptosis and inflammation of HG-treated HK-2 cells. Furthermore, miR-499a-5p targeted NRIP1 to inhibit its mRNA expression, and further suppressed its translation. NRIP1 was downregulated by hyperoside in a dose dependent manner. Finally, rescue assays indicated that miR-499a-5p inhibition rescued the protective effects of hyperoside on apoptosis and inflammatory response of HK-2 cells by NRIP1. In conclusion, our findings revealed that hyperoside alleviates HG-induced apoptosis and inflammatory response of HK-2 cells by the miR-499a-5p/NRIP1 axis.

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“…Now-a-days, ferroptosis is considered to be a primary cause of cell death related to a variety of disorders, including cancers, diabetes, neurodegenerative disorders, as well as renal failure Stockwell et al, 2017). A study showed that ferroptosis was activated in the streptozotocin-induced DBA/2J diabetic mice and HG cultured HK-2 cells (Li et al, 2021). ACSL4 (FACL4), the biomarker of ferroptosis, was not upregulated, and the expression of GPX-4 was not obviously altered in the HGHP group.…”

Section: Discussionmentioning

confidence: 99%

Tongxinluo preserves the renal function in diabetic kidney disease via protecting the HK-2 cells from the patterns of programmed cell death

Shen

Hou

2021

Bangladesh J Pharmacol

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This study was explored the renoprotective effect of Tongxinluo (a Traditional Chinese Medicine) on diabetic kidney disease and its underlying mechanism. The results revealed significant (p<0.05) up-regulation of the expression of Bcl-2 and down-regulation of NF-κB p-p65, ASC, NLRP3, caspase-1, cleaved GSDMD, IL-1β, caspase-3, Bax and the ratio of Bcl-2 and Bax in immortalized proximal tubular HK-2 cells cultured by hyperglycemia combined with hyperlipidemia. In db/db mice, Tongxinluo treatment substantially decreased the 24 hours albuminuria excretion rate and the urine albumin-creatinine ratios and renal morphologic abnormalities. Similarly, the levels of NF-κB p-p65, NLRP3, caspase-1, cleaved GSDMD, IL-1β, caspase-3, and the ratio of Bcl-2 and Bax were down-regulated by Tongxinluo treatment in the kidney samples of db/db mice (p<0.05). Taken together, according to the anti-pyroptosis and anti-apoptosis effect of Tongxinluo, it shows the potential to be effective for the treatment of diabetic kidney disease.

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Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy

Cited by 248 publications

References 47 publications

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Hyperoside Protects HK-2 Cells Against High Glucose-Induced Apoptosis and Inflammation via the miR-499a-5p/NRIP1 Pathway

Tongxinluo preserves the renal function in diabetic kidney disease via protecting the HK-2 cells from the patterns of programmed cell death

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