Targeting Mitochondria and Reactive Oxygen Species-Driven Pathogenesis in Diabetic Nephropathy

Lindblom, Runa; Higgins, Gavin C; Coughlan, Melinda T.; Haan, Judy B. de

doi:10.1900/rds.2015.12.134

Cited by 86 publications

(72 citation statements)

References 240 publications

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“…Oxidative stress plays a central role in the development of diabetic nephropathy (29,30). Hyperglycemia increases mitochondrial ROS, which is secondary to the up-regulation of certain NOX subunits that induce progression of diabetic kidney disease (31).…”

Section: Discussionmentioning

confidence: 99%

HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice

Yan

Huang

et al. 2016

Molecular Endocrinology

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Many studies have provided evidence to demonstrate the beneficial renal effects of resveratrol (RESV) due to its antioxidant character and its capacity for activation of surtuin 1. However, the molecular mechanisms underlying the protective role of RESV against kidney injury are still incompletely understood. The present study used Lepr db/db (db/db) and Lepr db/m (db/m) mice as models to evaluate the effect of RESV on diabetic nephropathy (DN). RESV reduced proteinuria and attenuated the progress of renal fibrosis in db/db mice. Treatment with RESV markedly attenuated the diabetes-induced changes in renal superoxide dismutase copper/zinc, superoxide dismutase manganese, catalase, and malonydialdehyde as well as the renal expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), α-smooth muscle actin (α-SMA), and E-cadherin in db/db mice. The kidney expression of the IGF-1 receptor (IGF-1R) was increased in db/db mice, but the expression of 3-hydroxy-3-methylglutaryl reductase degradation (HRD1), a ubiquitin E3 ligase, was significantly decreased in the DN model. RESV treatment dramatically decreased IGF-1R and increased HRD1 expressions, consistent with data obtained with HKC-8 cells. HRD1 physically interacted with IGF-1R in HKC-8 cells and liquid chromatography and tandem mass spectrometry (LC-MS/MS) data supported the concept that IGF-1R is one of the HRD1 substrates. HRD1 promoted the IGF-1R ubiquitination for degradation in HKC-8 cells, and the down-regulation of HRD1 reversed the protective effects of RESV in HKC-8 cells. In summary, we have demonstrated that RESV reduces proteinuria and attenuates the progression of renal fibrosis in db/db mice. These protective effects of RESV on DN were associated with the up-regulation of HRD1, induced by RESV, and the promotion of IGF-1R ubiquitination and degradation.

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Section: Discussionmentioning

confidence: 99%

HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice

Yan

Huang

et al. 2016

Molecular Endocrinology

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“…Oxidative stress is an important culprit in the pathogenesis [1,2] and progression [3][4][5] of CKD, but also in cardiovascular disease, a major complication of CKD and the major cause of death among patients undergoing dialysis treatment [16], as well as in diabetes mellitus, 1 important cause of CKD, in which it is well established that the intracellular environment is oxidized [1,17]. Importantly, CKD affects red blood cell and platelets that are activated and produce reactive oxygen species, which in turn activates intracellular redox enzymes, for example, superoxide dismutase, catalase, glutathione peroxidase, transferases, and glutathione reductase [6], showing and increased redox imbalance in platelets and red blood cells of CKD patients [5,6,[18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, CKD affects red blood cell and platelets that are activated and produce reactive oxygen species, which in turn activates intracellular redox enzymes, for example, superoxide dismutase, catalase, glutathione peroxidase, transferases, and glutathione reductase [6], showing and increased redox imbalance in platelets and red blood cells of CKD patients [5,6,[18][19][20][21]. Markers of protein and lipid peroxidation, for example, malondialdehyde (MDA/TBARS), advanced glycation end products including pentosidine [7,8], advanced oxidation protein products [1,5] are also altered in CKD; however, to date, there are no redox markers that are readily used in the point-of-care testing.…”

Section: Discussionmentioning

confidence: 99%

“…Acute and chronic kidney failure are associated with enhanced reactive oxygen species generation and impaired antioxidant defenses [1,2], starting already at early stages of chronic kidney disease (CKD) and increasing with as well as contributes to disease progression [3][4][5]. Several intracellular redox enzymes have been measured in red blood cells in kidney failure [6], and lipid peroxidation markers, glycation end products including pentosidine [7,8] as well as 8-hydroxy-2'doxyguanosine (8-OH-dG) [9] have been assessed as markers of oxidative stress and inflammation in CKD, however, as of yet, there is no simple method of measuring redox balance, suitable for a point of care setting.…”

Section: Introductionmentioning

confidence: 99%

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Serum Glutaredoxin Activity as a Marker of Oxidative Stress in Chronic Kidney Disease: A Pilot Study

Levin¹,

Nair

Qureshi³

et al. 2018

Nephron

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Background: Inflammation and oxidative stress play important roles in the pathogenesis and progression of chronic kidney disease (CKD) and in its complications, in particular cardiovascular disease, a major cause of death among patients undergoing dialysis treatment. We recently described that Glutaredoxin1 (Grx), an intracellular antioxidant, catalyzes oxidoreductase reactions also extracellularly, and that serum Grx levels correlate to disease severity in type 2 diabetes. Aim: In the current study we assess Grx as a potential clinical marker of oxidative stress in CKD. Methods: We examined Grx activity in 25 patients with different stages of chronic kidney failure, 19 control subjects, and 36 patients at initiation of dialysis and after 2 years of dialysis. Results: We found that Grx activity was significantly higher in CKD patients compared to control subjects, indicating an oxidized extracellular environment in CKD. Grx levels correlated to interleukin-6 and pentosidine, but not to age or GFR. In dialysis patients with Grx sampling before dialysis start and after 2 years of dialysis, Grx levels increased more in hemodialysis (HD) patients than in peritoneal dialysis patients, indicating an increased oxidative stress imbalance in HD patients. Patients who experienced a stroke or myocardial infarction at any time had a significantly higher increase in Grx during the 2 years of dialysis, compared to patients without stroke or myocardial infarction, indicating a possible association between high Grx levels and a cardiovascular event. Conclusion: Our pilot study indicates that Grx may be a useful marker for assessing the degree of oxidative stress in CKD, however this needs further investigation in a larger prospective patient cohort.

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“…In virtually all of these oxidative stress-linked dysfunctions, antioxidants have proven to be very valuable in their treatment [13,[16][17][18][19]. In addition to specific antioxidants such as coenzyme Q10, alpha lipoic acid and vitamin E, certain natural products have been shown to be effective treatments in regard to these specific diseases [20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Effects of Ganoderma Lucidum on Biochemical Dysfunctions of the Rabbit Urinary Bladder using an In-Vitro Model of Ischemia / Reperfusion

Levin¹,

Li²,

Wu³

et al. 2017

SDRP-JPS

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ABSTRACT:Background: Oxidative stress involving ischemia followed by reperfusion are major etiological factors in obstructive bladder dysfunction in both men and rabbits. Specific natural products such as Ganoderma lucidum with significant antioxidant activity have proven to be useful in their treatment. In two recent studies we demonstrated that pretreatment with Ganoderma was effective preventing bladder dysfunction using both invivo and in-vitro models of ischemia-reperfusion. The current study is a follow-up study using the in-vitro model of ischemia-reperfusion. Methods: Eight New Zealand White rabbits were divided into 2 groups. One group (Group-1) was fed Ganoderma (100 mg/Kg) daily for 3 weeks while the other group (Group-2) were given saline. At the end of a 3 week period, each rabbit was euthanized and the bladder separated into twelve full thickness strips and mounted in individual baths. After 1 hour in oxygenated Tyrodes with glucose, 4 strips from each group were removed frozen and stored at -80 o C. At this time, the oxygenated Tyrodes + glucose were changed to Tyrodes equilibrated with nitro gen in the absence of glucose (ischemia) for 1 hour. After 1 hour of ischemia the buffer was then changed back to normal oxygenated Tyrode's with glucose and allowed to recover for 2 hours (reperfusion). After this time period, the four remaining strips from each group were frozen and stored. The isolated strips were analyzed for the following biomarker enzymes: citrate synthase (mitochondria), calcium ATPase (intracellular calcium movement through the cell wall), and sarcoendoplasmic reticular ATPase (intracellular calcium uptake into the sarcoplasmic reticulum following stimulation. Results: Ischemia-reperfusion resulted in a significant decrease (~50%) in all three enzyme activities. Pretreating with Ganoderma protected all three enzyme activities which were approximately at control levels. Conclusion: Pretreatment of rabbits for three weeks with Ganoderma prior to subjecting them to invitro ischemia-reperfusion significantly protected the bladder enzymes.

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Targeting Mitochondria and Reactive Oxygen Species-Driven Pathogenesis in Diabetic Nephropathy

Cited by 86 publications

References 240 publications

HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice

HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice

Serum Glutaredoxin Activity as a Marker of Oxidative Stress in Chronic Kidney Disease: A Pilot Study

Effects of Ganoderma Lucidum on Biochemical Dysfunctions of the Rabbit Urinary Bladder using an In-Vitro Model of Ischemia / Reperfusion

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