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-Linolenic Acid, Suppress Deoxynivalenol-Induced Experimental IgA Nephropathy in Mice1
,,2
* Department of Food Science and Human Nutrition,
Department of Microbiology and Molecular Genetics, and
Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824
2To whom correspondence should be addressed. E-mail: pestka{at}msu.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-linolenic acid (ALA), were evaluated for efficacy in ameliorating the development of IgA nephropathy (IgAN) induced in mice by the mycotoxin deoxynivalenol (DON). The effects of DON were compared in mice that were fed for 18 wk with AIN-93G diets containing 1) 10 g/kg corn oil plus 60 g/kg oleic acid (control); 2) 10 g/kg corn oil plus 35 g/kg oleic acid and 25 g/kg DHA-enriched fish oil (DHA); 3) 10 g/kg corn oil plus 33 g/kg oleic acid and 27 g/kg EPA-enriched fish oil (EPA); and 4) 10 g/kg corn oil plus 37 g/kg oleic acid and 23 g/kg DHA + EPA (1:1) enriched fish oil (DHA + EPA). The DHA, EPA and DHA + EPA diets attenuated induction by dietary DON (10 mg/kg) of serum IgA and IgA immune complexes, kidney mesangial IgA deposition, and ex vivo IgA secretion by spleen cells. Consumption of the DHA + EPA diet for 8 wk significantly abrogated the DON-induced gene expression of interleukin (IL)-6, a requisite cytokine for DON-induced IgA nephropathy, in spleen and Peyer’s patches. Finally, incorporation of ALA-containing flaxseed oil up to 60 g/kg in the AIN-93G diet did not affect DON-induced IgA dysregulation in mice. Taken together, both DHA and EPA, but not ALA, ameliorated the early stages of IgAN, and these effects might be related to a reduced capacity for IL-6 production.
KEY WORDS: • immunoglobulin A nephropathy • deoxynivalenol • (n-3) fatty acid
IgA nephropathy (IgAN)3 is an immune complex disease that affects mainly children and young adults (1). About 20–40% of IgAN patients develop end-stage renal disease. High serum IgA and IgA immune complex (IgA-IC) concentrations are considered to be important contributing factors for IgAN (2–5). Serum IgA-IC, as well as dimeric and polymeric IgA, deposits in the kidney mesangium and likely causes inflammation by activating the complement via the alternative pathway (6).
Proposed therapeutic strategies for IgAN include decreasing the synthesis of IgA-IC, limiting mesangial IgA deposition, antagonizing the effects of platelet-derived growth factor and transforming growth factor , reducing the noxious glomerular injury due to infiltrating neutrophils (7), and blocking production of lipid inflammation mediators (8). Consumption of (n-3) PUFAs might be a promising nutritional treatment for IgAN based on their known anti-inflammatory effects (9–13). In the largest long-term clinical trial in high-risk patients with IgAN to date, consumption of fish oil supplements retarded IgAN progression to renal failure as evidenced by reduced inflammation and glomerulosclerosis (14). Another 4-y prospective study similarly showed that the (n-3) PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), had the same beneficial effects as fish oil on IgAN (15).
Deoxynivalenol (DON or vomitoxin) is a Type B trichothecene mycotoxin that is produced by the fungus Fusarium and is frequently encountered in cereal-based foods (16,17). DON and other trichothecenes disrupt leukocyte function by inhibiting translation as well as by inducing activation of mitogen-activated protein kinases (MAPKs), cytokine production, and apoptosis, all of which are dependent on the dose or concentration of the toxin (18). Dietary DON exposure dysregulates IgA production in mice, and this is characterized by high concentrations of serum IgA and IgA-IC as well as IgA deposition in the kidney, thus mimicking the early stages of IgAN (19–25).
Aberrant stimulation of the gut mucosal immune system with subsequent polyclonal activation of IgA-committed B cells to terminal differential appears to contribute to DON-induced IgA dysregulation (18,26). Although the gut acts as an entry to a vast array of foreign antigens, antibody responses are seldom induced because of oral tolerance, which is defined as the natural resistance to mount a strong antibody response to food and other antigens in the alimentary tract. Oral exposure of DON can induce proinflammatory cytokines, particularly interleukin (IL)-6, which might impair oral tolerance and ultimately lead to IgA-IC deposition in kidneys (27–31).
Experimental induction of IgAN by DON in mice provides an opportunity for studying early mechanisms and potential therapeutic regimens for human IgAN. Recently, our laboratory reported that consumption of menhaden fish oil blocked IgA dysregulation and IgA deposition in kidney during DON-induced IgAN (32). The purpose of this study was to assess in this experimental model the effects of consuming diets enriched with DHA, EPA, and -linolenic acid (ALA), the primary (n-3) PUFAs consumed by humans.
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MATERIALS AND METHODS |
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Animals. Male and female B6C3F1 mice (7–8 wk old), weighing between 20 and 25 g were obtained from Charles River. Housing, handling, and sample collection procedures conformed to the policies and recommendations of the Michigan State University Laboratory Animal Research Committee and were in accordance with guidelines established by the NIH. Mice were housed in environmentally protected transparent polypropylene cages with stainless steel wire tops for a period of 1 wk before induction of different treatments. The mice had free access to water. Experimental diets were placed in special containers to minimize spillage. Environmental conditions included 23–25°C, relative humidity of 45–55%, and a 12-h light:dark cycle.
Diets and experimental design. Experimental diets were based on the purified AIN-93G formulation (34), and had the following ingredients (per kg): 10 g AIN-93G mineral mix, 10 g AIN-93 vitamin mix, 200 g casein, 397.5 g cornstarch, 132 g Dyetrose (dextrinized cornstarch), 50 g cellulose, 3 g L-cystine, 2.5 g choline bitartrate, 14 mg tert-butylhydroquinone, and 100 g sucrose (Dyets). Different concentrations of fish and terrestrial plant oils were added at 70 g/kg as described in the following 3 studies.
In Study 1, corn oil, oleic acid (Dyets), DHA-enriched fish oil (containing 604 g/kg DHA, 71 g/kg EPA), EPA-enriched fish oil (540 g/kg EPA, 71 g/kg DHA) and DHA + EPA enriched fish oil (402 g/kg DHA, 341 g/kg EPA) (Ocean Nutrition) were used to modify the basal diet to yield 5 experimental groups (n = 10): Control, Control + DON, DHA + DON, EPA + DON and (DHA + EPA) + DON (Table 1). Diets were prepared every 2 wk, stored in aliquots at –20°C, and provided fresh to the mice each day. The final lipid compositions of the experimental diets are shown in Table 2. Male B6C3F1 mice were housed singly and fed the diets for 18 wk. Food intake was measured daily and body weight was monitored weekly. Blood was collected from the lateral saphenous vein (35) at 4- to 5-wk intervals for serum IgA and IgA-IC measurement. At wk 18, mice were anesthetized with methoxyfluorane and killed by cervical dislocation. Spleens and Peyer’s patches were removed aseptically for preparing cell cultures. Kidneys from each mouse were removed for immunohistochemical examination. Livers were used as surrogate tissues to measure cellular (n-3) PUFA incorporation.
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IgA and IgA-IC measurement. IgA was measured in serum by ELISA (19) using mouse reference Ig serum (Bethyl Laboratories), goat anti-mouse IgA (heavy chain–specific), and peroxidase-conjugated goat IgG fraction to mouse IgA (Organon Teknika). For detection of IgA-IC, diluted serum samples were first precipitated by 70 g/L polyethylene glycol (PEG 6000; Sigma) (37) and quantified by IgA ELISA (19).
IL-6 measurement. Mouse sera were analyzed for IL-6 as previously described by Moon and Pestka (38) using Immunolon IV removawell microtiter strips (Dynatech Laboratories), rat anti-mouse IL-6, biotinylated rat anti-mouse-IL-6, IL-6 standard (Pharmingen), horseradish peroxidase conjugated streptavidin (Sigma), and 3',3',5',5'-tetramethyl benzidine (Fluka Chemical) as substrate. Absorbance was read at 450 nm and IL-6 was quantified.
Assessment of kidney mesangial IgA deposition. Kidney sections were prepared and analyzed for IgA deposition according to Pestka et al. (23). Briefly, kidneys were frozen in liquid nitrogen, sectioned to 7 µm with a cryostat (Reichert-Jung, Cambridge Instruments), and stained for IgA deposition with fluorescein-labeled goat anti-mouse IgA (Sigma). IgA-associated immunofluorescence was assessed with a Nikon Labophot microscope equipped with a Kodak DC290 digital camera. Mean fluorescence intensity of 10 randomly selected glomeruli from each section was determined in polygons encircling the glomeruli using the UTHSCSA Image Tool Software V 1.2 (39). Pixels in the circled area were measured on a grayness scale that ranged from 0 (black) to 255 (white).
Cell cultures. Spleen and Peyer’s patch cell cultures were prepared as previously described (32). Supernatants were collected after 5 d and stored in aliquots at –20°C until analysis for IgA.
IL-6 mRNA measurement by competitive RT-PCR. RNA was extracted with Trizol reagent (Life Technologies) according to the manufacturer’s instructions. RNA from each sample was coreverse-transcribed to cDNA with a truncated IL-6 RNA internal standard constructed by the RT-PCR Competitor Construction Kit (Ambion). The cDNA was amplified in a 9600 Perkin Elmer Cycler (Perkin-Elmer) using the following parameters: 35 cycles of reactions of denaturation at 94°C for 30 s, annealing at 50°C for 45 s, and elongation at 72°C for 45 s. An aliquot of each PCR product was subjected to 1.5% agarose gel electrophoresis and visualized by staining with ethidium bromide. Primers were synthesized at Michigan State University Molecular Structure facility. The 5' forward and 3' reverse-complement PCR primers for amplification of mouse IL-6 cDNA were AAGAAAGACAAAGCCAGA and TTCGTAGAGAACAACATAA, respectively. The sizes of amplified IL-6 cDNA and its internal standard cDNA were 329 and 270 bp, respectively. The densitometric ratio of IL-6 cDNA:IL-6 internal standard was used to construct a standard curve to calculate IL-6 transcript concentrations in original sample.
Statistics. Data were analyzed using Sigma Stat for Windows (Jandel Scientific). Data were subjected to one-way ANOVA and pairwise comparisons made by Bonferroni or Student-Newman-Keuls methods. If data did not meet the normality assumption, they were subjected to Kruskal-Wallace ANOVA on Ranks, and pairwise comparisons were made by Dunn’s or Student-Newman-Keuls methods. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Study 2. A second study was conducted to determine whether feeding a diet containing DHA + EPA–enriched fish oil modulated DON-induced IL-6 expression. Here, a single acute oral exposure to DON was used to precisely control the timing of the exposure and the toxin dose. IL-6 mRNA concentrations in control and DHA + EPA groups not treated with DON were below the detection limit for competitive RT-PCR. As expected, acute oral exposure to DON induced significantly increased spleen and Peyer’s patch IL-6 mRNA expression in control mice (Fig. 5A,B). Earlier feeding with DHA + EPA eliminated this increase. Consistent with the mRNA data, DON upregulated serum IL-6 at 3 h post-DON exposure (Fig. 6). These effects were significantly reduced by earlier feeding with DHA + EPA. IL-6 concentrations in control and DHA + EPA groups were below the limit of detection.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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During the past 30 years, the ratio of (n-6) to (n-3) fatty acids in diets in industrialized societies has increased because of the increased consumption of vegetable oils rich in (n-6) PUFAs (44). In the United States, daily intake of ALA is 1.4 g and of DHA and EPA, 0.1–0.2 g. A recent estimate of the ratio of (n-6) to (n-3) PUFAs consumed is 9.8:1, which is much higher than the current recommendation (i.e., 2.3:1), which could be achieved by a 4-fold increase in fish consumption (45). All diets used here contained 70 g/kg total lipid with identical concentrations of (n-6) PUFA and energy density. In Studies 1 and 2, we adjusted the ratios of (n-6):(n-3) for control and (n-3) PUFA treatment groups to 16:1 and 1:1.8, respectively, thus encompassing the spectrum of low and recommended (n-3) PUFA consumption for U.S. consumers.
DON significantly retarded weight gain and lowered food intake throughout Study 1, which confirms the well-documented effects of DON on these 2 variables (16). These effects might relate to the capacity of DON to inhibit protein translation, upregulate proinflammatory cytokine expression, inhibit food intake, and decrease nutritional efficiency (18) and nutrient uptake (46). A key observation was that DON did not appear to affect (n-3) PUFA composition in livers of mice fed control diets. Although DON-fed control mice had significantly higher linoleic acid concentrations than mice fed the control diet alone, this did not appear to affect concentrations of arachidonic acid.
For these studies, commercial fish oil preparations that were highly enriched in EPA or DHA or that had equivalent concentrations of DHA and EPA were chosen. It is notable that at termination of Study 1, mice fed the 3 (n-3) PUFA diets had nearly equivalent amounts of DHA and EPA in livers. The similarities in (n-3) PUFA tissue concentrations among the 3 treatment groups is consistent with the lack of differences in suppression of DON-induced serum IgA. Equivalent concentrations of the 2 (n-3) PUFAs might have resulted from the following: 1) the presence of EPA in DHA-enriched oil and DHA in EPA-enriched oils, 2) efficient accumulation of DHA, and/or 3) metabolic conversion of DHA to EPA. A limitation of taking measurements after 18 wk is that these values might not reflect relative concentrations of DHA and EPA during early time points of the study. Different tissue concentrations of (n-3) PUFAs early in the experiment could affect ongoing and downstream IgA responses such as IgA-IC at wk 13 and mesangial IgA accumulation, suggesting that DHA was superior to EPA. Relative to the latter, it is notable that concentrations of arachidonic acid in the Study 3 diet groups followed a rank order of EPA > DHA + EPA > DHA (Table 2) and a similar trend was apparent in liver (Table 6). It is possible that arachidonic acid might antagonize (n-3) PUFA effects and thus be most apparent in EPA-fed mice. Further studies on the effects of dietary arachidonic acid on DON-induced IgAN are warranted
In Studies 1 and 3, serum IgA and IgA-IC were significantly increased after 8–9 wk of DON treatment rather than 4 wk as described in our previous study (32). It is important to note that the corn oil concentration in these studies was reduced from 50–70 g/kg to 10g/kg, which markedly reduced (n-6) PUFA concentrations but kept them equivalent among different experimental groups. Linoleic acid, which is a precursor of arachidonic acid, comprises 
600 g/kg of corn oil. Arachidonic acid can be metabolized to prostaglandin (PG)E2 in vivo, which may contribute to elevated production of IL-6 in vitro and in vivo (38), a cytokine that promotes the induction of IgA (31). Reducing the corn oil concentration in the basal diet could potentially result in a lower levels of PGE2 (47) and ultimately IL-6 and IgA. Nevertheless, significant DON-induced IgA and IgA-IC elevation was still observed in both Study 1 and Study 3, thus facilitating comparison of the efficacy of (n-3) PUFA therapeutic regimens.
The mechanism by which DON induces IgA dysregulation remains unclear. The gut mucosal compartment may be a primary target of DON (18). Antigenic specificity studies revealed that DON-induced serum IgA reacts with self and nonself antigens (24,48,49) and can be polyspecific, suggesting that DON breaks oral tolerance and promotes IgA production in response to food and self antigens (18). Consistent with this possibility, DON distributes into the lymphoid tissues (27) and has the potential to promote terminal differentiation of B cells to IgA secretion (30,50–53). Study 1 revealed that lymphoid cells from spleens of DON-fed mice secreted significantly more IgA than did those of the control group, which was also seen in earlier studies. Similar patterns were observed here for Peyer’s patches. The capacity of (n-3) PUFAs appears to interfere with IgA upregulation and suggests that they might enhance oral tolerance.
IL-6 is upregulated by DON in vitro (52,54,55) and in vivo (27–29); IL-6 is critical for promoting differentiation of IgA-committed cells to IgA secretion (56–60). Consistent with these findings, IL-6 is required for DON-induced IgA dysregulation (30,32). It is thus notable that in Study 2, feeding DHA + EPA for 8 wk significantly impaired DON-induced increases in serum IL-6 and IL-6 mRNA levels in spleen and Peyer’s patches. Accordingly, inhibition of IL-6 by (n-3) PUFAs may play an important role in their attenuation of DON-induced IgA dysregulation. This inhibition is likely to be (n-3) PUFA–specific because, in Study 1, mice fed corn oil + oleic acid had equivalent tissue concentrations of only the (n-6) PUFA, arachidonic acid, but were not resistant to induction of this cytokine by DON.
We observed that (n-3) PUFA treatments significantly reduced arachidonic acid and increased DHA and EPA as a percentage of total liver phospholipids, providing evidence that supplementation with (n-3) PUFA, modified the (n-6):(n-3) ratio in cell membranes. The modification of membrane phospholipids can change the eicosanoid profile (e.g., PGE2, leukotrieneB4) and secondary message molecules (diacylglycerol, ceramide, Ca2+). All of these factors can affect activation of intracellular kinases including phospholipase A, phosphokinase C, and MAPKs, as well as subsequent downstream gene expression (61). Similarly, macrophages from mice fed fish oil produce less PGE2, thromboxane B2, and IL-6 in response to lipopolysaccharide stimulation (62).
Cell membrane modification might contribute to (n-3) PUFA effects on immune system stimulation and IgA production in the model described in this study. DHA and EPA treatment prevents the recruitment of Ras protein to the membrane by changing the membrane structure and possibly by blocking activation of MAPKs (63). DHA can also affect protein palmitalation and prevent the recruitment of Src family kinases to the cell membrane (64). The latter generally cluster in the lipid raft through glycosyl phosphatidylinositol and are essential for T-cell activation. Mirnikjoo et al. (65) found that although DHA and EPA can inhibit protein kinase (PK)A, calmodulin 2, and PKC activation, arachidonic acid had no effect. Recently, Moon and Pestka (38) observed that both DHA and EPA were more effective than arachidonic acid in inhibiting DON-induced activation of MAPKs. Overall, we speculate that membrane-mediated cell signaling might be a key target for fish oil–derived (n-3) PUFAs, and this was ultimately manifested in suppression of DON-induced IgAN.
The (n-3) PUFA, ALA, is essential for humans and is derived mainly from terrestrial plant consumption. It is the principal precursor for EPA and DHA. In human and animal studies, ALA was shown to be as beneficial to cardiovascular health as EPA and DHA from marine and fish oils (66). However, the potential effects of ALA on IgAN remain unknown. Here, when flaxseed oil containing high concentrations of ALA was fed to mice, in the DON-induced IgAN model, it failed to inhibit DON-induced elevation of IgA. This result suggests that, among the (n-3) PUFAs, EPA and DHA are more biologically potent than ALA in preventing experimental IgAN. Although (n-3) PUFA incorporation was not measured in Study 3, rodents desaturate and elongate ALA to DHA and EPA, and elevation of the latter fatty acids with concurrent reductions in arachidonic acid in the mouse tissue would be expected (67). In a murine colon tumorigenesis model, Petrik et al. (68) found antitumorigenic effects of EPA and DHA, but not ALA, despite conversion by the latter to DHA and EPA. Thus unknown complexities remain with regard to the biological effects of long-chain (n-3) PUFA compared with ALA.
Taken together, the results of the 3 studies performed here suggest that both DHA and EPA, but not ALA, ameliorated the DON-induced IgA dysregulation and these effects might be related to a reduced capacity for IL-6 production. The experimental model described herein mimics primarily the early stages of IgAN related to IgA dysregulation rather than later stages that involve prominent kidney inflammation and injury. Our findings suggest that (n-3) PUFA supplementation might be helpful to persons diagnosed early with IgAN as well as persons with a familial history of the disease. Further insight is required into the molecular mode of action of (n-3) PUFAs in blocking IgA dysregulation as well as the role of IL-6 and other cytokines.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DON, deoxynivalenol; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IgA-IC, IgA immune complex; IgAN, IgA nephropathy; IL, interleukin; MAPKs, mitogen-activated protein kinases; PG, prostaglandin.
Manuscript received 29 December 2003. Initial review completed 15 February 2004. Revision accepted 22 March 2004.
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