Increased Oxidative Stress in the Mouse Adriamycin Model of Glomerulosclerosis Is Accompanied by Deposition of Ferric Iron and Altered GGT Activity in Renal Cortex

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

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Abstract TP102: Modulation of Neuroinflammation by Haptoglobin Reduces Oxidative Stress and Improves ICH Outcomes

Stroke ◽

10.1161/str.47.suppl_1.tp102 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Jenna Leclerc ◽

Alex Dang ◽

Juan Santiago-Moreno ◽

Sylvain Dore

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Functional Outcomes ◽

Ferric Iron ◽

Heme Oxygenase 1 ◽

High Morbidity ◽

Blood Components ◽

Autologous Whole Blood ◽

The Brain ◽

Histological Staining

Intracerebral hemorrhage (ICH) is a stroke subtype associated with high morbidity and mortality. With breakdown of the blood-brain barrier and entry of toxic blood components and metabolites within the brain, a highly oxidative environment ensues and leads to a toxic neuroinflammatory cascade. A major cause of the debilitation following brain hemorrhage is due to the direct toxicity of blood components, notably hemoglobin (Hb), the most upstream precipitating factor in the cascade. The acute phase plasma protein haptoglobin (Hp) binds Hb and inhibits its cytotoxic, pro-oxidative, and pro-inflammatory properties. In this study, we investigated whether the local and specific overexpression of Hp would aid in the safe detoxification and clearance of free Hb, thereby protecting the neuropil from Hb-mediated oxidative stress and improving ICH outcomes. Hp was overexpressed locally within the brain using uniquely designed adeno-associated viral vectors and ICH was induced using the intrastriatal autologous whole blood injection model. Functional outcomes were assessed by a 24-point neurological deficit score. At 72h post-hemorrhage, mice were sacrificed and brains collected for histological staining. Hp-overexpressing mice demonstrated smaller lesion volumes (p<0.05) with less blood accumulation (p<0.05) and improve neurologic status after ICH (p<0.05) when compared to an identically treated control group (n=11-13/group). Histological staining for Iba-1, GFAP, heme oxygenase-1, 4-hydroxynonenal, ferric iron, and myeloperoxidase was performed and revealed: 1) significantly less heme oxygenase-1 expression and lipid peroxidation, 2) a trend towards reduced peripheral neutrophil infiltration, 3) significantly increased cortical microgliosis and cortical and striatal astrogliosis, and 4) no changes in ferric iron content or striatal microgliosis. In conclusion, Hp overexpression in the brain reduces ICH-induced brain injury and improves functional outcomes. Locally modulating brain Hp levels could represent an important clinically relevant strategy for the treatment of ICH.

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6-gingerol ameliorates gentamicin induced renal cortex oxidative stress and apoptosis in adult male albino rats

Tissue and Cell ◽

10.1016/j.tice.2016.03.006 ◽

2016 ◽

Vol 48 (3) ◽

pp. 208-216 ◽

Cited By ~ 13

Author(s):

Ahmed M.S. Hegazy ◽

Mohammed M. Mosaed ◽

Saad H. Elshafey ◽

Naglaa A. Bayomy

Keyword(s):

Oxidative Stress ◽

Adult Male ◽

Renal Cortex ◽

Albino Rats

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An antioxidant role for catecholate siderophores in Salmonella

Biochemical Journal ◽

10.1042/bj20121771 ◽

2013 ◽

Vol 454 (3) ◽

pp. 543-549 ◽

Cited By ~ 33

Author(s):

Maud E. S. Achard ◽

Kaiwen W. Chen ◽

Matthew J. Sweet ◽

Rebecca E. Watts ◽

Kate Schroder ◽

...

Keyword(s):

Oxidative Stress ◽

Ferric Iron ◽

Iron Acquisition ◽

Oxygen Species ◽

Functional Studies ◽

Host Pathogen Interaction ◽

Host Pathogen ◽

Very High ◽

Full Protection

Iron acquisition is an important aspect of the host–pathogen interaction. In the case of Salmonella it is established that catecholate siderophores are important for full virulence. In view of their very high affinity for ferric iron, functional studies of siderophores have been almost exclusively focused on their role in acquisition of iron from the host. In the present study, we investigated whether the siderophores (enterobactin and salmochelin) produced by Salmonella enterica sv. Typhimurium could act as antioxidants and protect from the oxidative stress encountered after macrophage invasion. Our results show that the ability to produce siderophores enhanced the survival of Salmonella in the macrophage mainly at the early stages of infection, coincident with the oxidative burst. Using siderophore biosynthetic and siderophore receptor mutants we demonstrated that salmochelin and enterobactin protect S. Typhimurium against ROS (reactive oxygen species) in vitro and that siderophores must be intracellular to confer full protection. We also investigated whether other chemically distinct siderophores (yersiniabactin and aerobactin) or the monomeric catechol 2,3-dihydroxy-benzoate could provide protection against oxidative stress and found that only catecholate siderophores have this property. Collectively, the results of the present study identify additional functions for siderophores during host–pathogen interactions.

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Increased ferric iron content and iron-induced oxidative stress in the brains of scrapie-infected mice

Brain Research ◽

10.1016/s0006-8993(00)02907-3 ◽

2000 ◽

Vol 884 (1-2) ◽

pp. 98-103 ◽

Cited By ~ 53

Author(s):

Nam-Ho Kim ◽

Seok-Joo Park ◽

Jae-Kwang Jin ◽

Myung-Sang Kwon ◽

Eun-Kyoung Choi ◽

...

Keyword(s):

Oxidative Stress ◽

Iron Content ◽

Ferric Iron

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A maternal low-protein diet and neonatal overnutrition result in similar changes to glomerular morphology and renal cortical oxidative stress measures in male Wistar rats

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2018-0288 ◽

2019 ◽

Vol 44 (2) ◽

pp. 164-171 ◽

Cited By ~ 3

Author(s):

Anderson Pedroza ◽

Diorginis Soares Ferreira ◽

David F. Santana ◽

Pedro Thiago da Silva ◽

Francisco Carlos Amanajás de Aguiar Júnior ◽

...

Keyword(s):

Oxidative Stress ◽

Wistar Rats ◽

Renal Cortex ◽

Protein Diet ◽

Antioxidant Defenses ◽

Low Protein Diet ◽

Low Protein ◽

Oxidative Balance ◽

Male Wistar Rats ◽

Glomerular Morphology

There is a strong correlation between inadequate gestational and postpartum nutrition and the occurrence of cardiovascular diseases. The present study investigated the effects of a maternal low-protein diet and neonatal overfeeding on the oxidative balance and morphology of the renal cortex of male Wistar rats. Two independent protocols were used. First, pregnant Wistar rats received diets containing either 17% (normal protein) or 8% (low protein) casein throughout pregnancy and lactation. Second, the litter size was reduced by one-third on the third postnatal day to induce overnourishment in offspring. At 30 days, the oxidative balance and morphology of the renal cortex were analyzed. There was a small but significant increase in renal corpuscle area in the low protein (LP, 5%) and overnutrition (ON, 8%) groups. Glomerular tuft area also increased in LP (6%) and ON (9%), as did glomerular cellularity (LP, +11%; ON, +12%). In the oxidative stress analyses, both nutritional insults significantly elevated lipid peroxidation (LP, +18%; ON, +135%) and protein oxidation (LP, +40%; ON, +65%) while significantly reducing nonenzymatic antioxidant defenses, measured as reduced glutathione (LP, –32%; ON, –45%) and total thiol content (LP, –28%; ON, –24%). We also observed a decrease in superoxide dismutase (LP, –78%; ON, –51%), catalase (LP, –18%; ON, –61%), and glutathione S-transferase (only in ON, –44%) activities. Our results demonstrate that nutritional insults, even those of a very different nature, during perinatal development can result in similar changes in oxidative parameters and glomerular morphology in the renal cortex.

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Dietary (–)-epicatechin mitigates oxidative stress, NO metabolism alterations, and inflammation in renal cortex from fructose-fed rats

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2015.11.009 ◽

2016 ◽

Vol 90 ◽

pp. 35-46 ◽

Cited By ~ 43

Author(s):

Paula D. Prince ◽

Cecilia Rodríguez Lanzi ◽

Jorge E. Toblli ◽

Rosana Elesgaray ◽

Patricia I. Oteiza ◽

...

Keyword(s):

Oxidative Stress ◽

Renal Cortex

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Aging increases Oxidative Stress and Renal Expression of Oxidant and Antioxidant Enzymes that Are Associated with an Increased Trend in Systolic Blood Pressure

Oxidative Medicine and Cellular Longevity ◽

10.4161/oxim.2.3.8819 ◽

2009 ◽

Vol 2 (3) ◽

pp. 138-145 ◽

Cited By ~ 36

Author(s):

Pedro Gomes ◽

Sónia Simão ◽

Elisabete Silva ◽

Vanda Pinto ◽

João S. Amaral ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Lipid Peroxidation ◽

Renal Function ◽

Antioxidant Enzymes ◽

Systolic Blood Pressure ◽

Renal Cortex ◽

Antioxidant Defenses ◽

Wky Rats ◽

Old Rats

The aim of this study was to investigate whether the effects of aging on oxidative stress markers and expression of major oxidant and antioxidant enzymes associate with impairment of renal function and increases in blood pressure. To explore this, we determined age-associated changes in lipid peroxidation (urinary malondialdehyde), plasma and urinary hydrogen peroxide (H2O2) levels, as well as renal H2O2production, and the expression of oxidant and antioxidant enzymes in young (13 weeks) and old (52 weeks) male Wistar Kyoto (WKY) rats. Urinary lipid peroxidation levels and H2O2production by the renal cortex and medulla of old rats were higher than their young counterparts. This was accompanied by overexpression of NADPH oxidase components Nox4 and p22phoxin the renal cortex of old rats. Similarly, expression of superoxide dismutase (SOD) isoforms 2 and 3 and catalase were increased in the renal cortex from old rats. Renal function parameters (creatinine clearance and fractional excretion of sodium), diastolic blood pressure and heart rate were not affected by aging, although slight increases in systolic blood pressure were observed during this 52-week period. It is concluded that overexpression of renal Nox4 and p22phoxand the increases in renal H2O2levels in aged WKY does not associate with renal functional impairment or marked increases in blood pressure. It is hypothesized that lack of oxidative stress-associated effects in aged WKY rats may result from increases in antioxidant defenses that counteract the damaging effects of H2O2.

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Protective effects of the angiotensin II type I (ATI) receptor blockade in low-renin deoxycorticosterone acetate (DOCA)-treated spontaneously hypertensive rats

Clinical Science ◽

10.1042/cs20030299 ◽

2004 ◽

Vol 106 (3) ◽

pp. 251-259 ◽

Cited By ~ 13

Author(s):

Virginia CHAMORRO ◽

Rosemary WANGENSTEEN ◽

Juan SAINZ ◽

Juan DUARTE ◽

Francisco O'VALLE ◽

...

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Urinary Excretion ◽

Renal Injury ◽

Spontaneously Hypertensive Rats ◽

Ventricular Hypertrophy ◽

Renal Cortex ◽

Ang Ii ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

The present study evaluates the participation of oxidative stress, tissue angiotensin II (Ang II) and endothelin (ET) in the effects of losartan on blood pressure (BP), ventricular hypertrophy and renal injury in spontaneously hypertensive rats (SHRs), and explores how these effects are modified when spontaneous hypertension is transformed in a low-renin model by the administration of deoxycorticosterone acetate (DOCA). The following groups were used: SHR-control, SHR+DOCA, SHR+losartan and SHR+DOCA+losartan. Tail systolic BP was measured once a week. After 9 weeks of treatment, direct BP and metabolic, morphological, biochemical and renal variables were measured. DOCA administration to SHRs produced an increase in BP, ventricular hypertrophy, renal weight, proteinuria, renal histopathological lesions, urinary excretion of isoprostane F2α and ET levels in the renal cortex. Losartan reduced BP, plasma malondialdehyde levels, urinary excretion of isoprostane F2α, renal Ang II and renal and urinary levels of ET in the SHR and DOCA-treated SHR groups. Losartan increased plasma nitrite/nitrate in SHRs, but not in low-renin DOCA-treated SHRs. Losartan reduced ventricular hypertrophy and ventricular Ang II in SHRs, but not in DOCA-treated SHRs. Losartan significantly decreased proteinuria and renal injury in DOCA-treated SHRs. We conclude that (i) the DOCA-induced aggravation of hypertension, ventricular hypertrophy and renal injury in SHRs is accompanied by augmented oxidative stress and increased levels of ET in the renal cortex, which could contribute to their development; and (ii) losartan reduced oxidative stress and renal Ang II and ET in SHRs and DOCA-treated SHRs, which might contribute to its antihypertensive and renoprotective effects, regardless of renin status.

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Does Heat Shock Enhance Oxidative Stress? Studies with Ferrous and Ferric Iron

Radiation Research ◽

10.2307/3577841 ◽

1990 ◽

Vol 124 (3) ◽

pp. 288 ◽

Cited By ~ 37

Author(s):

Michael L. Freeman ◽

Douglas R. Spitz ◽

Michael J. Meredith

Keyword(s):

Oxidative Stress ◽

Heat Shock ◽

Ferric Iron ◽

Stress Studies

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