Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids

BackgroundRenal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy.MethodsMice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies.ResultsIn kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway.ConclusionsAOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.

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100 DIET AND FATTY ACID COMPOSITION OF BOVINE PLASMA, GRANULOSA CELLS, AND CUMULUS - OOCYTE COMPLEXES

Reproduction Fertility and Development ◽

10.1071/rdv17n2ab100 ◽

2005 ◽

Vol 17 (2) ◽

pp. 200 ◽

Cited By ~ 7

Author(s):

S. Adamiak ◽

M. Ewen ◽

J. Rooke ◽

R. Webb ◽

K. Sinclair

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Granulosa Cells ◽

Body Condition Score ◽

Peripheral Circulation ◽

Dietary Lipids ◽

Uptake Mechanism ◽

Fa Composition ◽

Total Fatty Acids

The effects of altering dietary carbohydrates and lipids to oocyte donors during superovulation and ovum pickup (OPU) on in vitro embryo production was reported previously (Adamiak et al. 2004 Reprod. Dev. Fert. 16, 193–194). Here we report the effects of these dietary treatments on the fatty acid (FA) composition of plasma, granulosa cells (GCs), and cumulus–oocyte complexes (COCs) from the 32 heifers used in that study. Blood samples were collected by jugular venipuncture. COCs and GCs were harvested from each heifer by OPU as described previously but were pooled between pairs of heifers within treatment to provide adequate material for FA analysis. Both GCs and COCs were washed twice in PBS supplemented with 0.3% (w/v) BSA (FA-free) before being transferred into 2 : 1 (v/v) chloroform : methanol solution for FA extraction. FA composition was determined using gas chromatography as described previously (Reis et al. 2002, Theriogenology 57, 507). Data were analyzed by ANOVA. Total plasma FA content averaged 1.12 μg/mL and was unaffected by body condition score (BCS). Low BCS heifers had more saturated (54.0 ± 1.76 vs. 49.2 ± 1.74%) and monounsaturated (22.4 ± 1.08 vs. 18.2 ± 0.69%) FA, but less polyunsaturated FA (PUFA) (23.7 ± 1.75 vs. 32.8 ± 2.21%) in plasma than moderate BCS heifers (P < 0.01). Animals fed high relative to low fiber diets had greater plasma FA (1.3 ± 0.15 vs. 1.0 ± 0.12 μg/mL) and PUFA (31.2 ± 2.56 vs. 25.3 ± 2.19%), but less monounsaturated FA (18.8 ± 1.04 vs. 21.5 ± 1.09%) (P < 0.01). Dietary protected lipid (Ca soaps of FA) increased plasma FA (1.6 ± 0.07 vs. 0.6 ± 0.04 μg/mL) and PUFA (30.0 ± 1.92 vs. 26.4 ± 3.03%) (P < 0.05), but reduced plasma saturated FA (48.9 ± 1.12 vs. 54.2 ± 2.14%; P < 0.01) in the animals fed high compared to low fiber diets, respectively. In contrast to their effects in plasma, BCS and diet had little effect on FA composition of GCs and COCs. Although low BCS and dietary lipids both increased FA in COCs (78.3 ± 2.01 vs. 69.2 ± 2.80, P < 0.01; and 77.1 ± 2.96 vs. 70.5 ± 2.26 ng/COC; P < 0.05, respectively), neither factor significantly altered the FA composition of COCs. Across treatments, the FA composition of GCs and COCs differed markedly from that of plasma (Table 1), confirming the presence of a selective uptake mechanism in the follicle that can moderate dietary induced fluctuations in FA supply from peripheral circulation. Table 1. Concentrations of fatty acids in plasma, GCs, and COCs expressed as mean percentages (w/w) of total fatty acids This work was supported by Defra and The Perry Foundation.

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Advanced oxidation protein products downregulate CYP1A2 and CYP3A4 expression and activity via the NF-κB-mediated signaling pathway in vitro and in vivo

Laboratory Investigation ◽

10.1038/s41374-021-00610-9 ◽

2021 ◽

Author(s):

Tianrong Xun ◽

Zhufen Lin ◽

Xiaokang Wang ◽

Xia Zhan ◽

Haixing Feng ◽

...

Keyword(s):

Liver Microsomes ◽

Advanced Oxidation ◽

Uremic Toxins ◽

Uremic Toxin ◽

Dependent Manner ◽

Advanced Oxidation Protein Products ◽

Protein Levels ◽

Cyp3a4 Expression

AbstractUremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6β-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/β, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/β/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes.

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Fructose-1,6-Bisphosphate and N-Acetylcysteine Attenuate the Formation of Advanced Oxidation Protein Products, a New Class of Inflammatory Mediators, In Vitro

Inflammation ◽

10.1007/s10753-012-9498-6 ◽

2012 ◽

Vol 35 (6) ◽

pp. 1786-1792 ◽

Cited By ~ 12

Author(s):

Guilherme Vargas Bochi ◽

Vanessa Dorneles Torbitz ◽

Lara Peruzzolo Cargnin ◽

Manuela Borges Sangoi ◽

Roberto Christ Vianna Santos ◽

...

Keyword(s):

Inflammatory Mediators ◽

Advanced Oxidation ◽

Advanced Oxidation Protein Products ◽

New Class ◽

Fructose 1,6 Bisphosphate

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Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol-rich beverage; a pilot clinical study with phytochemical and in vitro antioxidant characterization

Nutrition Journal ◽

10.1186/1475-2891-10-67 ◽

2011 ◽

Vol 10 (1) ◽

Cited By ~ 17

Author(s):

Boris V Nemzer ◽

Liliana C Rodriguez ◽

Linda Hammond ◽

Robert DiSilvestro ◽

John M Hunter ◽

...

Keyword(s):

Clinical Study ◽

Advanced Oxidation ◽

Advanced Oxidation Protein Products ◽

Pilot Clinical Study

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Advanced Oxidation Protein Products Induce Hypertrophy and Epithelial-To-Mesenchymal Transition in Human Proximal Tubular Cells through Induction of Endoplasmic Reticulum Stress

Cellular Physiology and Biochemistry ◽

10.1159/000369740 ◽

2015 ◽

Vol 35 (2) ◽

pp. 816-828 ◽

Cited By ~ 17

Author(s):

Xun Tang ◽

Guang Rong ◽

Yang Bu ◽

Shaojie Zhang ◽

Min Zhang ◽

...

Keyword(s):

Protein Expression ◽

Er Stress ◽

Total Protein ◽

Epithelial To Mesenchymal Transition ◽

Proximal Tubular Cells ◽

Advanced Oxidation Protein Products ◽

Mesenchymal Transition ◽

Tubular Cells ◽

Cell Hypertrophy ◽

Proximal Tubular

Background: In chronic kidney disease (CKD), the accumulation of advanced oxidation protein products (AOPPs) is prevalent. Hypertrophy and epithelial-to-mesenchymal transition (EMT) of tubular cells are associated with the pathogenesis of CKD. However, whether AOPPs induce tubular-cell hypertrophy and EMT is unclear. In this study, we investigated the effect of AOPPs on human proximal tubular cells (HK-2 cells) and the mechanisms underlying tubular-cell hypertrophy and EMT in vitro. Methods: The mRNA and protein expression of CCAAT/enhancer-binding protein-homologous protein (CHOP), glucose-regulated protein (GRP) 78, p27, α-smooth muscle actin (α-SMA) and E-cadherin were evaluated by quantitative real-time PCR and western blot, respectively. Cell cycle was detected by flow cytometry. Bicinchoninic acid method was performed to measure total protein content. Results: AOPP treatment upregulated total protein expression, caused an increase in the percentage of G1-phase cells, and induced the overexpression of p27 and α-SMA, lowered the expression of E-cadherin. Furthermore, AOPP treatment induced the overexpression of GRP78 and CHOP. Moreover, the aforementioned effects were reversed following the treatment of cells with an NADPH oxidase inhibitor, a reactive oxygen species (ROS) scavenger, or salubrinal, which is an inhibitor of ER stress, whereas these effects were produced after exposure to thapsigargin, an inducer of ER stress. Conclusion: Our results suggest that AOPPs induced HK-2-cell hypertrophy and EMT by inducing ER stress, which was likely mediated by ROS. These findings could facilitate the development of novel therapeutic strategies for suppressing the progression of CKD.

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Docosahexaenoic and Eicosapentaenoic Acids Prevent Altered-Muc2 Secretion Induced by Palmitic Acid by Alleviating Endoplasmic Reticulum Stress in LS174T Goblet Cells

Nutrients ◽

10.3390/nu11092179 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2179

Author(s):

Quentin Escoula ◽

Sandrine Bellenger ◽

Michel Narce ◽

Jérôme Bellenger

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Palmitic Acid ◽

Er Stress ◽

Unsaturated Fatty Acids ◽

Saturated Fatty Acids ◽

Goblet Cells ◽

The Impact

Diets high in saturated fatty acids (FA) represent a risk factor for the development of obesity and associated metabolic disorders, partly through their impact on the epithelial cell barrier integrity. We hypothesized that unsaturated FA could alleviate saturated FA-induced endoplasmic reticulum (ER) stress occurring in intestinal secretory goblet cells, and consequently the reduced synthesis and secretion of mucins that form the protective mucus barrier. To investigate this hypothesis, we treated well-differentiated human colonic LS174T goblet cells with palmitic acid (PAL)—the most commonly used inducer of lipotoxicity in in vitro systems—or n-9, n-6, or n-3 unsaturated fatty acids alone or in co-treatment with PAL, and measured the impact of such treatments on ER stress and Muc2 production. Our results showed that only eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids protect goblet cells against ER stress-mediated altered Muc2 secretion induced by PAL, whereas neither linolenic acid nor n-9 and n-6 FA are able to provide such protection. We conclude that EPA and DHA could represent potential therapeutic nutrients against the detrimental lipotoxicity of saturated fatty acids, associated with type 2 diabetes and obesity or inflammatory bowel disease. These in vitro data remain to be explored in vivo in a context of dietary obesity.

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Advanced oxidation protein products upregulate efflux transporter expression and activity through activation of the Nrf-2-mediated signaling pathway in vitro and in vivo

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2020.105342 ◽

2020 ◽

Vol 149 ◽

pp. 105342 ◽

Cited By ~ 1

Author(s):

Tianrong Xun ◽

Zhufen Lin ◽

Xia Zhan ◽

Shaolian Song ◽

Liqian Mo ◽

...

Keyword(s):

Signaling Pathway ◽

Advanced Oxidation ◽

Efflux Transporter ◽

Advanced Oxidation Protein Products ◽

Transporter Expression ◽

Expression And Activity

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Oleate attenuates palmitate-induced endoplasmic reticulum stress and apoptosis in placental trophoblasts

Reproduction ◽

10.1530/rep-16-0576 ◽

2017 ◽

Vol 153 (4) ◽

pp. 369-380 ◽

Cited By ~ 11

Author(s):

Bryanne N Colvin ◽

Mark S Longtine ◽

Baosheng Chen ◽

Maria Laura Costa ◽

D Michael Nelson

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Maternal Blood ◽

Dietary Fatty Acids ◽

Obese Women ◽

Villous Trophoblast ◽

The Unfolded Protein Response

Pre-pregnancy obesity is increasingly common and predisposes pregnant women and offspring to gestational diabetes, pre-eclampsia, fetal growth abnormalities and stillbirth. Obese women exhibit elevated levels of the two most common dietary fatty acids, palmitate and oleate, and the maternal blood containing these nutrients bathes the surface of trophoblasts of placental villi in vivo. We test the hypothesis that the composition and concentration of free fatty acids modulate viability and function of primary human villous trophoblasts in culture. We found that palmitate increases syncytiotrophoblast death, specifically by caspase-mediated apoptosis, whereas oleate does not cause enhanced cell death. Importantly, exposure to both fatty acids in equimolar amounts yielded no increase in death or apoptosis, suggesting that oleate can protect syncytiotrophoblasts from palmitate-induced death. We further found that palmitate, but not oleate or oleate with palmitate, increases endoplasmic reticulum (ER) stress, signaling through the unfolded protein response, and yielding CHOP-mediated induction of apoptosis. Finally, we show that oleate or oleate plus palmitate both lead to increased lipid droplets in syncytiotrophoblasts, whereas palmitate does not. The data show palmitate is toxic to human syncytiotrophoblasts, through the induction of ER stress and apoptosis mediated by CHOP, whereas oleate is not toxic, abrogates palmitate toxicity and induces fat accumulation. We speculate that our in vitro results offer pathways by which the metabolic milieu of the obese pregnant woman can yield villous trophoblast dysfunction and sub-optimal placental function.

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