Role of atrial natriuretic peptide in controlling diabetic nephropathy in rats

Abstract Background Diabetes is a downregulator of atrial natriuretic peptide (ANP), resulting in reduced nitric oxide level and low expression of endothelial nitric oxide synthase by which nitric oxide level get reduced. In the present study, we examined the role of ANP in reduced nitric oxide level, which may be responsible in controlling diabetic nephropathy in rats. Methods Serum nitrite/nitrate ratio, blood urea nitrogen, protein in urine, urinary output, serum creatinine, serum cholesterol, kidney weight, kidney hypertrophy, renal cortical collagen content, thiobarbituric acid level, and antioxidant enzymatic activities were assessed. Results Treatment with lisinopril (1 mg/kg) significantly attenuated diabetes-induced elevated glucose level, cholesterol level, and protein in urine concentration. Whereas ANP at low dose (5 μg/kg) has no effect on elevated markers of diabetic nephropathy, treatment with intermediate (10 μg/kg) and high-dose ANP (20 μg/kg) significantly attenuated the diabetes-induced increased blood urea nitrogen, protein in urine, urinary output, creatinine, cholesterol, kidney weight, kidney hypertrophy, renal collagen content, and thiobarbituric acid level and reduced endogenous antioxidant enzymatic activities. High dose of ANP was more effective in attenuating the diabetes-induced nephropathy, renal oxidative stress, and antioxidant enzyme activity as compared with the treatment with low-dose ANP (5 μg/kg), intermediate-dose ANP (10 μg/kg), or lisinopril (1 mg/kg, employed as standard agent). Administration of erythro-9-(2-hydroxy-3-nonyl)adenine, a phosphodiesterase-2 inhibitor (3 mg/kg), in combination with high-dose ANP significantly attenuated high-dose ANP induced ameliorative effects in diabetic nephropathy. Conclusions Taken together, these results indicate that diabetes-induced oxidative stress and lipid alterations may be responsible for the induction of nephropathy in diabetic rats. ANP at intermediate and high doses have prevented the development of diabetes-induced nephropathy by reducing the cholesterol level, protein in urine concentration, and renal oxidative stress and by increasing the nitrite/nitrate ratio, certainly providing the direct nephroprotective action.

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Enhancing kidney DDAH-1 expression by adenovirus delivery reduces ADMA and ameliorates diabetic nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00518.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. F509-F517 ◽

Cited By ~ 4

Author(s):

Michael D. Wetzel ◽

Ting Gao ◽

Kristen Stanley ◽

Timothy K. Cooper ◽

Sidney M. Morris ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Diabetic Nephropathy ◽

Fluorescent Protein ◽

Thiobarbituric Acid ◽

Renal Tissue ◽

Diabetic Mice ◽

Patients With Diabetes ◽

Green Fluorescent ◽

Stage Renal Disease

Endothelial dysfunction, characterized by reduced bioavailability of nitric oxide and increased oxidative stress, is a hallmark characteristic in diabetes and diabetic nephropathy (DN). High levels of asymmetric dimethylarginine (ADMA) are observed in several diseases including DN and are a strong prognostic marker for cardiovascular events in patients with diabetes and end-stage renal disease. ADMA, an endogenous endothelial nitric oxide synthase (NOS3) inhibitor, is selectively metabolized by dimethylarginine dimethylaminohydrolase (DDAH). Low DDAH levels have been associated with cardiac and renal dysfunction, but its effects on DN are unknown. We hypothesized that enhanced renal DDAH-1 expression would improve DN by reducing ADMA and restoring NOS3 levels. DBA/2J mice injected with multiple low doses of vehicle or streptozotocin were subsequently injected intrarenally with adenovirus expressing DDAH-1 (Ad-h-DDAH-1) or vector control [Ad-green fluorescent protein (GFP)], and mice were followed for 6 wk. Diabetes was associated with increased kidney ADMA and reduced kidney DDAH activity and DDAH-1 expression but had no effect on kidney DDAH-2 expression. Ad-GFP-treated diabetic mice showed significant increases in albuminuria, histological changes, glomerular macrophage recruitment, inflammatory cytokine and fibrotic markers, kidney ADMA levels, and urinary thiobarbituric acid reactive substances excretion as an indicator of oxidative stress, along with a significant reduction in kidney DDAH activity and kidney NOS3 mRNA compared with normal mice. In contrast, Ad-h-DDAH-1 treatment of diabetic mice reversed these effects. These data indicate, for the first time, that DDAH-1 mediates renal tissue protection in DN via the ADMA-NOS3-interaction. Enhanced renal DDAH-1 activity could be a novel therapeutic tool for treating patients with diabetes.

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Oxidative stress, histopathological and electron microscopic alterations induced by dimethylnitrosamine in renal male mice and the protective effect of α-lipoic acid

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2016-0042 ◽

2017 ◽

Vol 28 (2) ◽

Cited By ~ 1

Author(s):

Reham Z. Hamza ◽

Hayat A.A. Ismail ◽

Nahla S. El-Shenawy

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Lipid Peroxidation ◽

Uric Acid ◽

Lipoic Acid ◽

Low Dose ◽

Renal Tissue ◽

High Dose ◽

Male Mice ◽

Dose Treatment

AbstractBackground:Dimethylnitrosamine (DMN) is a waste product of several industrial processes. α-Lipoic acid (ALA) is a vitamin-like chemical also called as an antioxidant. Therefore, the study was designed to investigate the potential benefits of ALA in reducing the nephropathy of DMN in male mice.Methods:Animals were divided into 6 groups (n=8) and received their treatment for 4 weeks as follows: groups 1–4 served as control, ALA-treatment (16.12 mg/kg), DMN low dose treatment and DMN high dose treatment, respectively. Groups 5 and 6 received ALA before DMN low dose and DMN high dose, respectively. Superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, total antioxidant capacity, nitric oxide, lipid peroxidation as well as the levels of uric acid and creatinine were determined. The histological and ultrastructure changes of renal tissue were also evaluated.Results:Treatment of the DMN mice with ALA showed a reduction in the levels of kidney nitric oxide, lipid peroxidation, as well as creatinine and uric acid levels as compared with the DMN group. The results show that ALA plays an important role in quenching the free radicals resulting from the metabolism of DMN, thereby inhibiting lipid peroxidation and protecting membrane lipids from oxidative damage and, in turn, preventing oxidative stress and apoptosis. Histopathological and ultrastructure analysis of renal tissue confirmed the oxidative stress results occurred in DMN renal mice. Concomitant administration of ALA with DMN significantly decreased all the histopathological changes induced by DMN.Conclusions:The present study elucidated the therapeutic effects of ALA administered in combination with DMN to minimize its renal toxicity.

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A meta-analysis of biomarkers related to oxidative stress and nitric oxide pathway in migraine

Cephalalgia ◽

10.1177/0333102414564888 ◽

2015 ◽

Vol 35 (10) ◽

pp. 931-937 ◽

Cited By ~ 28

Author(s):

Monica Neri ◽

Alessandra Frustaci ◽

Mirta Milic ◽

Vanessa Valdiglesias ◽

Massimo Fini ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitrosative Stress ◽

Meta Analysis ◽

Thiobarbituric Acid ◽

Oxidative And Nitrosative Stress ◽

Pubmed Database ◽

Synthase Inhibitor ◽

Meta Analyses

Background Oxidative and nitrosative stress are considered key events in the still unclear pathophysiology of migraine. Methods Studies comparing the level of biomarkers related to nitric oxide (NO) pathway/oxidative stress in the blood/urine of migraineurs vs. unaffected controls were extracted from the PubMed database. Summary estimates of mean ratios (MR) were carried out whenever a minimum of three papers were available. Nineteen studies were included in the meta-analyses, accounting for more than 1000 patients and controls, and compared with existing literature. Results Most studies measuring superoxide dismutase (SOD) showed lower activity in cases, although the meta-analysis in erythrocytes gave null results. On the contrary, plasma levels of thiobarbituric acid reactive substances (TBARS), an aspecific biomarker of oxidative damage, showed a meta-MR of 2.20 (95% CI: 1.65–2.93). As for NOs, no significant results were found in plasma, serum and urine. However, higher levels were shown during attacks, in patients with aura, and an effect of diet was found. The analysis of glutathione precursor homocysteine and asymmetric dimethylarginine (ADMA), an NO synthase inhibitor, gave inconclusive results. Conclusions The role of the oxidative pathway in migraine is still uncertain. Interesting evidence emerged for TBARS and SOD, and concerning the possible role of diet in the control of NOx levels.

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The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis

Medicinski pregled ◽

10.2298/mpns1012827r ◽

2010 ◽

Vol 63 (11-12) ◽

pp. 827-832 ◽

Cited By ~ 7

Author(s):

Tatjana Radosavljevic ◽

Dusan Mladenovic ◽

Danijela Vucevic ◽

Rada Jesic-Vukicevic

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Reactive Oxygen Species ◽

Liver Injury ◽

Kupffer Cells ◽

Reactive Oxygen ◽

Oxygen Species ◽

Severe Liver ◽

Hepatocellular Necrosis

Introduction. Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. Role of oxidative stress in paracetamol-induced liver injury. The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils, Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in paracetamol-induced oxidative stress. The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mito?chondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonu?cleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. Role of Kupffer cells in paracetamol-induced liver injury. Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. Role of neutrophils in paracetamol-induced liver injury. Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. Role of peroxynitrite in paracetamol-induced oxidative stress. Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. Conclusion. Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species.

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Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes

Clinical Science ◽

10.1042/cs20120330 ◽

2012 ◽

Vol 124 (3) ◽

pp. 191-202 ◽

Cited By ~ 111

Author(s):

Mona Sedeek ◽

Alex Gutsol ◽

Augusto C. Montezano ◽

Dylan Burger ◽

Aurelie Nguyen Dinh Cat ◽

...

Keyword(s):

Body Weight ◽

Low Dose ◽

Transforming Growth Factor ◽

Disease Process ◽

Thiobarbituric Acid ◽

Transforming Growth Factor Β ◽

Mitogen Activated Protein Kinase ◽

High Dose ◽

Diabetic Mice ◽

Mitogen Activated Protein

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.

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Possible dual role of nitric oxide in oxidative stress injury: A study in perfused hepatocytes

International Journal of Immunopharmacology ◽

10.1016/s0192-0561(97)00048-9 ◽

1997 ◽

Vol 19 (9-10) ◽

pp. 599-605 ◽

Cited By ~ 9

Author(s):

H. Farghali ◽

S. Hynie ◽

Z. Vohnikova ◽

K. Masek

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Dual Role ◽

Stress Injury ◽

Oxidative Stress Injury

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Dyslipdemia induced by chronic low dose co-exposure to lead, cadmium and manganese in rats: the role of oxidative stress

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2017.06.017 ◽

2017 ◽

Vol 53 ◽

pp. 199-205 ◽

Cited By ~ 7

Author(s):

Olusola Olalekan Oladipo ◽

Joseph Olusegun Ayo ◽

Suleiman Folorunsho Ambali ◽

Bisalla Mohammed ◽

Tanang Aluwong

Keyword(s):

Oxidative Stress ◽

Low Dose

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The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy

Journal of Medical Biochemistry ◽

10.2478/v10011-008-0019-y ◽

2008 ◽

Vol 27 (3) ◽

pp. 376-382 ◽

Cited By ~ 5

Author(s):

Tatjana Cvetković ◽

Predrag Vlahović ◽

Vidosava đorđević ◽

Lilika Zvezdanović ◽

Dušica Pavlović ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Diabetic Nephropathy ◽

Urine Concentration ◽

Control Group ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Urinary Markers ◽

Stress Markers

The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy Oxidative stress is considered to be a unifying link between diabetes mellitus (DM) and its complications, including nephropathy (DN). The aim of this study was to determine the parameters of oxidative injury of lipids and proteins as well as the activity of ectoenzymes in the urine of DN patients. The study included 40 individuals: 10 patients with type 2 diabetes mellitus and microalbuminuria (DMT2-MIA), 10 type 2 diabetic patients with macroalbuminuria (DMT2-MAA), 10 patients with type 1 diabetes and microalbuminuria (DMT1-MIA) and 10 age- and sex-matched healthy subjects (control). In the urine we determined TBA reactive substances (TBARS), reactive carbonyl groups (RCG), and the activity of ectoenzymes N-acetyl-β-d-glucosaminidase (NAG), plasma cell differentiation antigen (PC-1), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV). A higher concentration of TBARS in the urine was found in DMT2-MIA and DMT1-MIA, compared to the control group (p<0.001 and P<0.05). The urine concentration of RCD shows similar results with a significant elevation in the groups with DMT2-MAA and DMT1-MIA, compared to the DMT2-MIA (p<0.001) and control group (p<0.001). Activities of NAG, APN and DPPIV were significantly higher in the urine of DMT2-MAA, compared to the control (p<0.01). The activity of PC-1 was slightly increased in that group, but not significantly. In conclusion, the level of oxidative stress markers and activities of brush border ectoenzymes in the urine may be a useful non-invasive and easily repeatable test in DN.

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Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/1806344 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Yang Zhang ◽

Weifang Liu ◽

Yanqi Zhong ◽

Qi Li ◽

Mengying Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Nlrp3 Inflammasome ◽

Low Dose ◽

Therapeutic Potential ◽

Metabolic Phenotypes ◽

Pyrin Domain ◽

Underlying Mechanisms ◽

And Oxidative Stress ◽

Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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