Umbelliferone delays the progression of diabetic nephropathy by inhibiting ferroptosis through activation of the Nrf-2/HO-1 pathway

Jin, Tong‐Shou; Chen, Cheng

doi:10.1016/j.fct.2022.112892

“…7 Oxidative Medicine and Cellular Longevity Nuclear factor erythroid 2-related factor 2 (NRF2) was a transcription factor of various antioxidant genes including GPX4, and it is known to suppress oxidative stress and ferroptosis [55][56][57]. Some studies found that activating NRF2 can significantly improve renal damage and inhibit ferroptosis in mice by upregulating GPX4 [23,58], which suggested that ferroptosis, specially NRF2/GPX4 axis, played an important role in the progression of DKD. It is of interest to further investigate the role of NRF2/GPX4 axis in the development of DKD.…”

Section: Discussionmentioning

confidence: 99%

Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Wang

¹

,

Chang

²

,

Zhao

³

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Background. Diabetic kidney disease (DKD) represents a heavy burden in type 2 diabetes mellitus (T2DM). Ferroptosis plays an important role in DKD, and it thus provides new perspectives to pursue more related biomarkers to assess the disease severity and prognosis. Glutathione peroxidase 4 (GPX4) is the mainstay in regulating ferroptosis. The current study investigated the predictive value of kidney GPX4 expression level in DKD progression. Methods. We measured GPX4 levels in kidney paraffin sections of 85 biopsy-proven DKD patients by immunohistochemistry staining. The associations between the GPX4 level and clinicopathological parameters as well as renal outcomes were analyzed. Results. GPX4 is mainly expressed in kidney tubulointerstitium, especially in tubular epithelial cells of DKD patients. The GPX4 expression level was significantly lower in DKD patients than healthy controls. Besides, GPX4 level significantly correlated with proteinuria ( r = − 0.42 , p < 0.001 ), urinary albumin-to-creatinine ratio (uACR) ( r = − 0.40 , p < 0.01 ), serum creatinine (Scr) ( r = − 0.59 , p < 0.001 ), estimated glomerular filtration rate (eGFR) ( r = 0.66 , p < 0.001 ), and the percentage of sclerosed glomeruli ( r = − 0.42 , p < 0.001 ) in renal specimens. During follow-up, the GPX4 level positively correlated with eGFR slope ( r = 0.48 , p < 0.001 ), and GPX4-low patients showed a significantly higher probability of developing end-stage kidney disease (ESKD) compared with GPX4-high patients ( p < 0.01 ). Moreover, after adjusting for other potential predictors, the GPX4 level was still an independent predictor of developing ESKD (HR 2.15, 95% CI 1.08 to 4.28, p < 0.05 ). Conclusions. Kidney tubulointerstitial GPX4 expression level was associated with the disease severity and progression of DKD.

show abstract

“…ACSL4 is a kind of fatty-acid-CoA ligases and is pro-ferroptosis by shaping cellular lipid composition ( 42 ). Interfering ACSL4 protein level either by pharmacological inhibitor ( 43 , 44 ) or by intrinsic active factors ( 45 ) is involved in ferroptosis in diabetic complications. Consistent with previous reports, we found significant ACSL4 elevation both in vivo and in vitro , and GSK-J4 could reverse its elevation.…”

Section: Discussionmentioning

confidence: 99%

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

Xu

¹

,

Liu

²

,

Wen

³

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Changes in modern lifestyle provoke a series of metabolic stresses such as hyperlipidemia. Excessive free fatty acids induce cardiomyocyte metabolic reprogramming and rearrangement of the lipid content of cardiomyocyte and promote oxidative stress. As a newly defined lipid peroxidation-related cell death pathway, the role of ferroptosis in metabolic stress-induced cardiomyocyte injury is poorly revealed. Our work indicates that GSK-J4, a histone lysine demethylase 6A/6B dual inhibitor, can alleviate palmitic acid (PA)-induced hypersensitivity to ferroptosis by suppressing H3K27 demethylation. Mechanistically, PA stimulation reduces the H3K27me3 level and hence promotes the expression of ACSL4, a key lipid modulator of ferroptosis. GSK-J4 pretreatment significantly preserves the H3K27me3 level and reduces the ACSL4 level. GSK-J4 also reduces reactive oxygen species to alleviate oxidative stress, which further decreases lipid peroxidation. Taken together, our data suggest that cardiomyocyte undergoes epigenetic reprogramming under metabolic challenges, rearranging lipid content, and sensitizing to ferroptosis. GSK-J4 can be a potential drug for treating hyperlipidemia-induced cardiomyocyte injury by targeting epigenetic modulations.

show abstract

“…At present, in clinical practice the progression of DN is delayed by controlling blood glucose and blood pressure, but the progression to ESRD cannot be completely prevented. Therefore, investigating the exact pathogenesis of DN is a key link to effectively intervening in its progress, and the development of new DRUGS to treat DN is also very critical at present [17]. Traditional Chinese medicine play an increasingly important role in the treatment of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Trifolirhizin relieves renal injury in a diabetic nephropathy model by inducing autophagy and inhibiting oxidative stress through the regulation of PI3K/AKT/mTOR pathway

Xin¹,

Xu²,

Yuan³

et al. 2022

Trop. J. Pharm Res

2

0

View full text Add to dashboard Cite

Purpose: To evaluate the effects of trifolirhizin on diabetic nephropathy (DN), and the mechanism of action. Methods: Male db/db mice (8 weeks, n = 24) and age-matched control mice (n = 6) were obtained. The mice were further divided into four groups and administered increasing doses of trifolirhizin (0, 12.5, 25 and 50 mg/kg). Histological analysis of renal tissues were performed by H & E staining. Blood urea nitrogen (BUN) and creatinine were determined using enzyme-linked immunosorbent assay (ELISA). Immunoblot and TUNEL assay were performed to investigate the effect of trifolirhizin on autophagy and apoptosis, while ELISA and dihydroethidium (DHE) staining were conducted to evaluate reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) levels. The effect of trifolirhizin on PI3K/AKT/mTOR pathway was determined using Immunoblot assays. Results: Trifolirhizin alleviated renal injury in diabetic mice, and also activate autophagy and inhibited apoptosis in the renal tissues in diabetic mice (p < 0.001). In addition, trifolirhizin inhibited the oxidative stress response in the renal tissue in diabetic mice (p < 0.001). Trifolirhizin further inhibited PI3K/AKT/mTOR pathway and therefore relieved renal injury in the diabetic nephropathy model (p < 0.001). Conclusion: Trifolirhizin alleviates renal injury in diabetic mice, activates autophagy, and inhibits apoptosis in renal tissue of diabetic mice. Therefore, trifolirhizin is a promising a promising drug for the treatment of DN.

show abstract

Umbelliferone delays the progression of diabetic nephropathy by inhibiting ferroptosis through activation of the Nrf-2/HO-1 pathway

Cited by 64 publications

References 55 publications

Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

Trifolirhizin relieves renal injury in a diabetic nephropathy model by inducing autophagy and inhibiting oxidative stress through the regulation of PI3K/AKT/mTOR pathway

Contact Info

Product

Resources

About