scholarly journals Extracellular Superoxide Dismutase Attenuates Renal Oxidative Stress Through the Activation of Adenosine Monophosphate-Activated Protein Kinase in Diabetic Nephropathy

2018 ◽  
Vol 28 (17) ◽  
pp. 1543-1561 ◽  
Author(s):  
Yu Ah Hong ◽  
Ji Hee Lim ◽  
Min Young Kim ◽  
Yaeni Kim ◽  
Hoon Suk Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Diabetic Nephropathy ◽  
Protein Kinase ◽  
Adenosine Monophosphate ◽  
Extracellular Superoxide Dismutase

scholarly journals The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62

2019 ◽  
Vol 5 (4) ◽  
pp. eaav4570 ◽  
Author(s):  
Daqian Xu ◽  
Xinjian Li ◽  
Fei Shao ◽  
Guishuai Lv ◽  
Hongwei Lv ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Kinase Activity ◽  
Survival Rates ◽  
Adenosine Monophosphate ◽  
Nuclear Accumulation ◽  
Protein Kinase Activity ◽  
Reduction Cell ◽  
Expression Of Genes

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5′-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62’s aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis

2002 ◽  
Vol 282 (4) ◽  
pp. L719-L726 ◽  
Author(s):  
Russell P. Bowler ◽  
Mike Nicks ◽  
Karrie Warnick ◽  
James D. Crapo
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Immunohistochemical Staining ◽  
Extracellular Superoxide Dismutase ◽  
Wild Type ◽  
Injured Lung ◽  
Intracellular Oxidative Stress

Bleomycin administration results in well-described intracellular oxidative stress that can lead to pulmonary fibrosis. The role of alveolar interstitial antioxidants in this model is unknown. Extracellular superoxide dismutase (EC-SOD) is the primary endogenous extracellular antioxidant enzyme and is abundant in the lung. We hypothesized that EC-SOD plays an important role in attenuating bleomycin-induced lung injury. Two weeks after intratracheal bleomycin administration, we found that wild-type mice induced a 106 ± 25% increase in lung EC-SOD. Immunohistochemical staining revealed that a large increase in EC-SOD occurred in injured lung. Using mice that overexpress EC-SOD specifically in the lung, we found a 53 ± 14% reduction in bleomycin-induced lung injury assessed histologically and a 17 ± 6% reduction in lung collagen content 2 wk after bleomycin administration. We conclude that EC-SOD plays an important role in reducing the magnitude of lung injury from extracellular free radicals after bleomycin administration.

Effects of oxidative stress on the nuclear translocation of extracellular superoxide dismutase

2003 ◽  
Vol 303 (3) ◽  
pp. 914-919 ◽  
Author(s):  
Tomomi Ookawara ◽  
Hironobu Eguchi ◽  
Masashi Nishimura ◽  
Takako Kizaki ◽  
Eiji Takayama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Nuclear Translocation ◽  
Extracellular Superoxide Dismutase

Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure

2006 ◽  
Vol 291 (2) ◽  
pp. H914-H920 ◽  
Author(s):  
Shinichiro Iida ◽  
Yi Chu ◽  
Robert M. Weiss ◽  
Yu Ming Kang ◽  
Frank M. Faraci ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Superoxide Dismutase ◽  
Gene Transfer ◽  
Coronary Artery Ligation ◽  
Extracellular Superoxide Dismutase ◽  
Gene Variant ◽  
Vascular Effects ◽  
Common Gene ◽  
Increased Risk

A common gene variant of human extracellular superoxide dismutase (ecSOD), in ∼5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSODR213G) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSODR213G, or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 ± 4% relaxation, means ± SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 ± 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 ± 0.2 to 0.9 ± 0.2 relative light units per second per millimeter squared (RLU·s−1·mm−2)] and peroxynitrite (from 2.4 ± 0.2 to 0.9 ± 0.1 RLU·s−1·mm−2) in the aorta from rats with heart failure. Gene transfer of ecSODR213G produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSODR213G in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSODR213G in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSODR213G.

scholarly journals Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy

2021 ◽  
Vol 22 (11) ◽  
pp. 5491
Author(s):  
Yuya Takahashi ◽  
Tatsunori Shimizu ◽  
Shunsuke Kato ◽  
Mitsuhiko Nara ◽  
Yumi Suganuma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Diabetic Nephropathy ◽  
Muscle Regeneration ◽  
Diabetic Mouse ◽  
Skeletal Muscle Regeneration ◽  
Oxidative Stress Marker ◽  
Regeneration Capacity ◽  
Cross Sectional

Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.

scholarly journals The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

2018 ◽  
Vol 29 (4) ◽  
pp. 1108-1127 ◽  
Author(s):  
Yaeni Kim ◽  
Ji Hee Lim ◽  
Min Young Kim ◽  
Eun Nim Kim ◽  
Hye Eun Yoon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
High Glucose ◽  
Receptor Agonist ◽  
Intracellular Ca ◽  
Intracellular Pathways

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor–α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase–β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)– and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose–treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKβ/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose–induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.

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