scholarly journals SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy

2018 ◽  
Vol 60 (2) ◽  
pp. 145-157 ◽  
Author(s):  
Huan Zhang ◽  
Xiuxia Liu ◽  
Shanshan Zhou ◽  
Ye Jia ◽  
Ying Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Critical Role ◽  
Antioxidant Defense System ◽  
Related Factor ◽  
Diabetic Mice ◽  
Nrf2 Protein

c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125’s protection against DN. To test the role of NRF2 in SP600125’s effect, streptozotocin-induced C57BL/6 wild-type (WT) and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125’s protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced Keap1 expression.

scholarly journals Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC

2017 ◽  
Vol 232 (1) ◽  
pp. 71-83 ◽  
Author(s):  
Wenpeng Dong ◽  
Ye Jia ◽  
Xiuxia Liu ◽  
Huan Zhang ◽  
Tie Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Sodium Butyrate ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Heme Oxygenase 1 ◽  
Transcriptional Level ◽  
Related Factor ◽  
Diabetic Mice ◽  
Hdac Activity

Oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN). Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in cellular defense against oxidative stress. NRF2 activators have shown promising preventive effects on DN. Sodium butyrate (NaB) is a known activator of NRF2. However, it is unknown whether NRF2 is required for NaB protection against DN. Therefore, streptozotocin-induced diabetic C57BL/6 Nrf2 knockout and their wild-type mice were treated in the presence or absence of NaB for 20 weeks. Diabetic mice, but not NaB-treated diabetic mice, developed significant renal oxidative damage, inflammation, apoptosis, fibrosis, pathological changes and albuminuria. NaB inhibited histone deacetylase (HDAC) activity and elevated the expression of Nrf2 and its downstream targets heme oxygenase 1 and NAD(P)H dehydrogenase quinone 1. Notably, deletion of the Nrf2 gene completely abolished NaB activation of NRF2 signaling and protection against diabetes-induced renal injury. Interestingly, the expression of Kelch-like ECH-associated protein 1, the negative regulator of NRF2, was not altered by NaB under both diabetic and non-diabetic conditions. Moreover, NRF2 nuclear translocation was not promoted by NaB. Therefore, the present study indicates, for the first time, that NRF2 plays a key role in NaB protection against DN. Other findings suggest that NaB may activate Nrf2 at the transcriptional level, possibly by the inhibition of HDAC activity.

scholarly journals Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system

2018 ◽  
Vol 293 (47) ◽  
pp. 18242-18269 ◽  
Author(s):  
Kelsey Murphy ◽  
Killian Llewellyn ◽  
Samuel Wakser ◽  
Josef Pontasch ◽  
Natasha Samanich ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant System ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Nuclear Translocation ◽  
Growth Factor Receptor ◽  
Antioxidant Defense System ◽  
Related Factor ◽  
Dependent Manner ◽  
Amyloid Aβ

Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood–brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7-kDa cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmol of mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and β-amyloid (Aβ) peptide–stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.

scholarly journals Redox Signaling in Diabetic Nephropathy: Hypertrophy versus Death Choices in Mesangial Cells and Podocytes

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Gina Manda ◽  
Alexandru-Ionel Checherita ◽  
Maria Victoria Comanescu ◽  
Mihail Eugen Hinescu
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Mesangial Cells ◽  
Antioxidant Response ◽  
Molecular Networks ◽  
Integrative Approach ◽  
Renal Cells ◽  
Diagnosis And Prognosis ◽  
New Therapeutic Approaches

This review emphasizes the role of oxidative stress in diabetic nephropathy, acting as trigger, modulator, and linker within the complex network of pathologic events. It highlights key molecular pathways and new hypothesis in diabetic nephropathy, related to the interferences of metabolic, oxidative, and inflammatory stresses. Main topics this review is addressing are biomarkers of oxidative stress in diabetic nephropathy, the sources of reactive oxygen species (mitochondria, NADPH-oxidases, hyperglycemia, and inflammation), and the redox-sensitive signaling networks (protein kinases, transcription factors, and epigenetic regulators). Molecular switches deciding on the renal cells fate in diabetic nephropathy are presented, such as hypertrophyversusdeath choices in mesangial cells and podocytes. Finally, the antioxidant response of renal cells in diabetic nephropathy is tackled, with emphasis on targeted therapy. An integrative approach is needed for identifying key molecular networks which control cellular responses triggered by the array of stressors in diabetic nephropathy. This will foster the discovery of reliable biomarkers for early diagnosis and prognosis, and will guide the discovery of new therapeutic approaches for personalized medicine in diabetic nephropathy.

scholarly journals Ethyl Vanillin Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting Oxidative Stress and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yuna Tong ◽  
Shan Liu ◽  
Rong Gong ◽  
Lei Zhong ◽  
Xingmei Duan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Cell Apoptosis ◽  
Cell Model ◽  
Critical Role ◽  
Kidney Injury ◽  
Related Factor ◽  
Ethyl Vanillin

Diabetes-induced oxidative stress and apoptosis is regarded as a critical role in the pathogenesis of diabetic nephropathy (DN). Treating diabetes-induced kidney damage and renal dysfunction has been thought a promising therapeutic option to attenuate the development and progression of DN. In this study, we investigated the renoprotective effect of ethyl vanillin (EVA), an active analogue of vanillin isolated from vanilla beans, on streptozotocin- (STZ-) induced rat renal injury model and high glucose-induced NRK-52E cell model. The EVA treatment could strongly improve the deterioration of renal function and kidney cell apoptosis in vivo and in vitro. Moreover, treating with EVA significantly decreased the level of MDA and reactive oxygen species (ROS) and stabilized antioxidant enzyme system in response to oxidative stress by enhancing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro. Furthermore, EVA also markedly suppressed cleaved caspase-3, Bax, and nuclear transcription factor erythroid 2-related factor (Nrf2) expression in STZ-induced rats. Therefore, these results of our investigation provided that EVA might protect against kidney injury in DN by inhibiting oxidative stress and cell apoptosis.

Salvia miltiorrhiza Lipophilic Fraction Attenuates Oxidative Stress in Diabetic Nephropathy through Activation of Nuclear Factor Erythroid 2-Related Factor 2

2017 ◽  
Vol 45 (07) ◽  
pp. 1441-1457 ◽  
Author(s):  
Lin An ◽  
Mei Zhou ◽  
Faiz M. M. T. Marikar ◽  
Xue-Wen Hu ◽  
Qiu-Yun Miao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Mesangial Cells ◽  
Salvia Miltiorrhiza ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor

Diabetic nephropathy (DN) is a common cause of chronic kidney disease and end-stage renal disease, which can be triggered by oxidative stress. In this study, we investigated the renoprotective effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on DN and examined the underlying molecular mechanism. We observed that EASM treatment attenuated metabolic abnormalities associated with hyperglycemic conditions in the experimental DN model. In streptozotocin (STZ)-induced mice, EASM treatment reduced albuminuria, improved renal function and alleviated the pathological alterations within the glomerulus. To mimic the hyperglycemic conditions in DN patients, we used high glucose (25[Formula: see text]mmol/L) media to stimulate mouse mesangial cells (MMCs), and EASM inhibited high glucose-induced reactive oxygen species. We also observed that EASM enhanced the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), which mediated the anti-oxidant response, and its downstream gene heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) with concomitant decrease of expression of kelch-like ECH-associated protein 1 (keap1) both in vitro and in vivo. Taken together, these results suggest that EASM alleviates the progression of DN and this might be associated with activation of Nrf2.

scholarly journals The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation

2020 ◽  
Vol 295 (21) ◽  
pp. 7350-7361 ◽  
Author(s):  
William P. Miller ◽  
Siddharth Sunilkumar ◽  
Joseph F. Giordano ◽  
Allyson L. Toro ◽  
Alistair J. Barber ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Antioxidant Response ◽  
Glycogen Synthase Kinase ◽  
Related Factor ◽  
Diabetic Mice ◽  
Antioxidant Genes ◽  
Deficient Mice

The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.

scholarly journals Role of Endothelial Nitric Oxide Synthase in Diabetic Nephropathy: Lessons from Diabetic eNOS Knockout Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Takamune Takahashi ◽  
Raymond C. Harris
Keyword(s):  
Animal Model ◽  
Diabetic Nephropathy ◽  
Critical Role ◽  
Therapeutic Interventions ◽  
Diabetic Mice ◽  
Model Study ◽  
Animal Model Study ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in many countries. The animal models that recapitulate human DN undoubtedly facilitate our understanding of this disease and promote the development of new diagnostic markers and therapeutic interventions. Based on the clinical evidence showing the association of eNOS dysfunction with advanced DN, we and others have created diabetic mice that lack eNOS expression and shown that eNOS-deficient diabetic mice exhibit advanced nephropathic changes with distinct features of progressive DN, including pronounced albuminuria, nodular glomerulosclerosis, mesangiolysis, and arteriolar hyalinosis. These studies clearly defined a critical role of eNOS in DN and developed a robust animal model of this disease, which enables us to study the pathogenic mechanisms of progressive DN. Further, recent studies with this animal model have explored the novel mechanisms by which eNOS deficiency causes advanced DN and provided many new insights into the pathogenesis of DN. Therefore, here we summarize the findings obtained with this animal model and discuss the roles of eNOS in DN, unresolved issues, and future investigations of this animal model study.

scholarly journals Inhibition of TRIM32 Attenuates the Apoptosis, Oxidative Stress and Inflammatory Injury of Podocytes Induced by High Glucose by Affecting the Akt/GSK-3β/Nrf2 Pathway

2021 ◽  
Author(s):  
Zhao Chen ◽  
Lifang Tian ◽  
Li Wang ◽  
Xiaotao Ma ◽  
Fuqian Lei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Protective Effects ◽  
Gsk 3Β ◽  
Induced Apoptosis

Abstract Hyperglycemia-induced oxidative stress of podocytes exerts a major role in the pathological process of diabetic nephropathy. Tripartite motif-containing protein 32 (TRIM32) has been reported as a key protein in the modulation of cellular apoptosis and oxidative stress under various pathological processes. However, whether TRIM32 participates in the regulation of high glucose (HG)-induced injury in podocytes has not been investigated. The aims of this work were to assess the possible role of TRIM32 in mediating HG-induced apoptosis, oxidative stress and inflammatory response in podocytes in vitro. Herein, our results showed a marked increase in TRIM32 expression in HG-exposed podocytes. Loss-of-function experiments showed that the knockdown of TRIM32 improved the viability of HG-stimulated podocytes, and suppressed HG-induced apoptosis, oxidative stress and inflammatory response in podocytes. Further investigation revealed that the inhibition of TRIM32 enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling associated with modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis in podocytes following HG exposure. However, the suppression of Akt abrogated the TRIM32-knockdown-mediated activation of Nrf2 in HG-exposed podocytes. In addition, the knockdown of Nrf2 markedly abolished the TRIM32-inhibition-induced protective effects in HG-exposed podocytes. In summary, the results of this work show that the inhibition of TRIM32 protects podocytes from HG-induced injury by potentiating Nrf2 signaling via the modulation of Akt/GSK-3β signaling. This study indicates a potential role of TRIM32 in mediating podocyte injury during the progression of diabetic nephropathy.

scholarly journals Dimethyl fumarate accelerates wound healing under diabetic conditions

2018 ◽  
Vol 61 (4) ◽  
pp. 163-172 ◽  
Author(s):  
Ying Li ◽  
Fuzhe Ma ◽  
Huimin Li ◽  
Yuguo Song ◽  
Huan Zhang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Oxidative Damage ◽  
Critical Role ◽  
Dimethyl Fumarate ◽  
Related Factor ◽  
Diabetic Wound ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Diabetic Wound Healing

Impaired wound healing is a common complication among patients with diabetes mellitus (DM), resulting in high rates of disability and mortality. Recent findings highlighted the critical role of nuclear factor erythroid 2-related factor 2 (NRF2) – a master of cellular antioxidants scavenging excessive DM-induced free radicals – in accelerating diabetic wound healing. Dimethyl fumarate (DMF) is a potent NRF2 activator used for the treatment of multiple sclerosis. However, the effect of DMF on wound healing has not been determined. The present study investigated the effect of DMF on the diabetic and the non-diabetic wound healing in streptozotocin-induced diabetic mice and non-diabetic control mice. DMF activated NRF2 signaling under both conditions. Interestingly, DMF attenuated oxidative damage and inflammation and accelerated wound closure in diabetic mice. However, this effect was not observed in non-diabetic mice. Keratinocytes were treated with normal glucose (NG), high glucose (HG) or hydrogen peroxide (H2O2), in the presence or absence of DMF to assess the role of reactive oxygen species (ROS) – inducible in DM – in mediating DMF-induced protection. Both HG and H2O2 elevated ROS, oxidative damage and inflammation, the effects of which were similarly blunted by DMF. However, in spite of the activation of NRF2, DMF lost this capability under the NG condition. The findings of this study demonstrate that ROS activate the protective effect of DMF on the diabetic wound healing.

Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice

2013 ◽  
Vol 304 (1) ◽  
pp. E87-E99 ◽  
Author(s):  
Wenpeng Cui ◽  
Bing Li ◽  
Yang Bai ◽  
Xiao Miao ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Effect ◽  
Mechanistic Study ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Diabetic Mice ◽  
Proteasomal Activity ◽  
Nrf2 Activation ◽  
Renal Tubular

Oxidative stress is a major cause of diabetic nephropathy. Upregulation of the key antioxidative transcription factor, nuclear factor-erythroid 2-related factor 2 (Nrf2), was found to prevent the development of diabetic nephropathy. The present study was designed to explore the therapeutic effect of Nrf2 induced by proteasomal inhibitor MG132 at a low dose (10 μg/kg) on diabetic nephropathy. Transgenic type 1 diabetic (OVE26) mice displayed renal dysfunction with albuminuria by 3 mo of age, at which time MG132 treatment was started. After 3-mo treatment with MG132, renal function, morphology, and biochemical changes were examined with real-time PCR, Western blotting, and immunohistochemical examination. Compared with age-matched, nontreated diabetic mice, MG132-treated diabetic mice showed significant improvements in terms of renal structural and functional alterations. These therapeutic effects were associated with increased Nrf2 expression and transcriptional upregulation of Nrf2-regulated antioxidants. Mechanistic study using human renal tubular HK11 cells confirmed the role of Nrf2, as silencing the Nrf2 gene with its specific siRNA abolished MG132 prevention of high-glucose-induced profibrotic response. Furthermore, diabetes was found to significantly increase proteasomal activity in the kidney, an effect that was significantly attenuated by 3 mo of treatment with MG132. These results suggest that MG132 upregulates Nrf2 function via inhibition of diabetes-increased proteasomal activity, which can provide the basis for the therapeutic effect of MG132 on the kidney against diabetes-induced oxidative damage, inflammation, fibrosis, and eventual dysfunction.

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