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J Am Soc Nephrol 14:389-396, 2003
© 2003 American Society of Nephrology

Docosahexaenoic Acid Ameliorates Murine Ischemic Acute Renal Failure and Prevents Increases in mRNA Abundance for both TNF-{alpha} and Inducible Nitric Oxide Synthase

Mariusz L. Kielar*, D. Rohan Jeyarajah{dagger}, X. J. Zhou{dagger} and Christopher Y. Lu*,§

*Departments of Internal Medicine, Division of Nephrology, {dagger}Surgery, Division of GI/Endocrine Surgery, {ddagger}Pathology, and §Graduate Program in Immunology, University of Texas Southwestern Medical Center, Dallas, Texas.

Correspondence to Dr. Christopher Y. Lu, Division of Nephrology, Dept. of Internal Medicine, U. Texas Southwestern Medical Center, Dallas, TX 75390-8856. Phone: (214)-648-2889; Fax: (214) 648-2071;


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. This study demonstrates that intraperitoneal injections of DHA (all cis 4,7,10,13,16,19 docosahexaenoic acid C22: n-3) bound to bovine serum albumin ameliorate murine acute renal failure (ARF) induced by temporary occlusion of the renal artery. Three micromoles of DHA decreased serum creatinine (Scr) from 2.3 mg/dl to 1.1 mg/dl 24 h after reperfusion (n = 15; P < 0.05). Scr of the treated animals were significantly lower than controls throughout a 7-d time course. Although lower doses of DHA were less effective, higher doses were not more effective. Ribonuclease (RNase) protection assays showed that ischemia increased mRNA abundance for TNF-{alpha} and inducible nitric oxide synthase (iNOS) at 24 h. This increase was prevented by DHA administration. Because TNF-{alpha} and iNOS contribute to renal ischemic injury, their inhibition may contribute to DHA’s salutary effect. In addition, the data may have therapeutic implications, because the DHA improves ARF even when administered at 4 h after reperfusion. Email: christopher.lu@utsouthwestern.edu


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Ischemic acute renal failure (ARF) remains a major clinical problem. The morbidity and mortality of affected patients remain high (1). In addition, ischemic injury to the renal allograft contributes to delayed allograft function and perhaps also initiates rejection (2,3).

Although the etiology of ischemic ARF is complex (see reviews, references 1 and 4–8), TNF-{alpha} and inducible nitric oxide synthase (iNOS) are two of many regulatory molecules that contribute to injury. TNF-{alpha} is produced by the kidney after renal ischemia in vivo (see review, reference 9) and by hypoxic LL-CPK1 renal tubule cells in vitro (10). Injury is ameliorated by TNF-{alpha} receptor antagonists (11) or anti–TNF-{alpha} monoclonal antibodies (12).

In addition to TNF-{alpha}, iNOS also contributes to injury. iNOS (NOS-2) is an isoform of nitric oxide synthase found in renal tubules, vascular smooth muscle, fibroblasts, and macrophages (13). Its gene expression is increased after ischemic ARF, and persistent high concentrations of NO result. In the presence of reactive oxygen species also found after renal ischemia, these persistent high concentrations of NO are converted into toxic peroxynitrite that oxidizes lipids, damages DNA, and modifies proteins by nitrating tyrosine residues. Three strategies that lower peroxynitrite concentration ameliorate ischemic renal injury. These three strategies were directly scavenging peroxynitrite, preventing the formation of peroxynitrite by scavenging reactive oxygen species, or inhibiting iNOS by specific pharmacologic agents, antisense, or transgenic knockout (see review, reference 14). Although most published data are consistent with the above hypothesis on the action of iNOS, one study (15) suggests that iNOS acts by increasing production of heat shock proteins.

The toxic effects of the persistent high concentrations of NO produced by iNOS are in contrast to the salutary vasodilatory effects of the transient low concentrations of NO produced by eNOS (NOS-1), an isoform of nitric oxide synthase found in endothelial cells (14). Such opposite (toxic versus salutary) effects of NO, depending on the kinetics of production, concentration, and chemical microenvironment, have been described in many situations, in addition to ischemic ARF (see review, reference 16).

DHA (all cis 4,7,10,13,16,19 docosahexaenoic acid C22: n-3) may inhibit production of TNF-{alpha} and activation of the iNOS gene; it is thus, on the basis of the above discussion, expected to ameliorate ischemic ARF. Long-term dietary supplementation with DHA or DHA-containing fish oils (17–23) decreases TNF-{alpha} production. Such diets also ameliorate ischemic ARF in dogs (24). However, such long-term dietary manipulation of TNF-{alpha} would not be useful in treating ARF, which is usually acute and unexpected. On the basis of our previous studies (25,26), we knew that DHA:BSA complexes acted rapidly and were not toxic in vitro. We now report that intraperitoneal injections of DHA in this form prevent increased abundance of TNF-{alpha} mRNA and also ameliorated injury after renal ischemia.

In addition to inhibiting TNF-{alpha}, we previously reported that DHA:BSA inhibited production of iNOS by macrophages in vitro (26,27). We now report that intraperitoneal injections of DHA:BSA also inhibit renal iNOS gene activation after ischemia. These findings may have therapeutic implications, particularly because the DHA may be given several hours after ischemia-reperfusion injury.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Complexes of BSA with DHA or Other Fatty Acids (DHA: BSA)
DHA (catalog #90310; Cayman Chemical Company, Ann Arbor, MI) was dissolved in absolute ethanol (20 mg/ml); 50 µl was added dropwise to 1 ml of delipidated, endotoxin-free BSA (0.1 g/ml, catalog # A8806; Sigma Chemical Company, St. Louis, MO). This mixture was vortexed for 2 min and incubated at 37°C for 2 h. This yielded a clear solution that was diluted to the appropriate DHA concentration, and 1 cc was injected intraperitoneally. Complexes of BSA and arachidonic acid (Cayman Chemical Company) were prepared in a similar manner. This procedure resulted in complexes consisting of fatty acid molecules bound to two of the three high-affinity hydrophobic pockets of albumin (28) and has previously been described by our group (25,26); improper procedure will result in a cloudy suspension of fatty acid micelles, which are toxic.

Renal Ischemia
We followed the animal care guidelines of the National Institutes of Health and the University of Southwestern Medical Center. Male 6- to 8-wk-old C3H/Hen mice (Harlan, Indianapolis, IN) were anesthetized with inhaled isoflurane (Foran, Baxter Healthcare Corp., Deerfield, IL), and the body temperature was maintained at 37°C using a rectal probe and a heating pad. Ischemia was induced by clamping both renal pedicles for 20 min with a 25-mm microaneurysm clamp. After removal of clamps, the muscle and skin were sutured separately. A light coat of Nexaband tissue adhesive (Veterinary Products Laboratories, Phoenix, AZ) was applied over the skin suture.

Ribonuclease Protection Assay
Kidneys were removed from some mice 24 h after reperfusion, frozen in liquid nitrogen, and stored at -70°C until RNA extraction using a RNeasy Midi Kit (catalog #75144; Qiagen, Valencia, CA). Whole frozen tissue was homogenized for 45 s in a guanidinium isothiocyanate (GITC) lysis buffer. After samples were centrifuged and supernatant was isolated, one volume of 70% ethanol was added. Samples were then added to the RNA extraction column. After elution of RNA with Rnase-free water, samples were quantified using a spectrophotometer at a wavelength of 260 nm.

The probes were made using the In Vitro Transcription Kit (catalog #45004K; Pharmingen). The template was mCK-3b (Pharmingen) and a custom-made iNOS probe. Thirty micrograms of total RNA was used for each lane. The protocol and reagents for the RNase treatment was provided by the Riboquant RPA kit (catalog #45014K; Pharmingen). After purification of RNA hybrids, the samples were run on a polyacrylamide gel (8 M urea/6% acrylamide:bis-acrylamide [19:1]). After drying, the gel was exposed on a phosphor image screen and analyzed with a Molecular Dynamics Storm 820 Phosphorimager.

Measurement of Serum Creatinine (Scr)
Blood was collected when the kidney was harvested or by retroorbital bleeding (150 µl of whole blood). Serum creatinine was measured using Beckman Creatinine Analyzer.

Histologic Examination
Three animals in DHA/BSA and BSA groups were sacrificed for morphologic studies. Immediately after sacrifice, the kidneys were removed, sectioned, and postfixed in 10% buffered formalin. The fixed tissues were imbedded in paraffin; 4-µm sections were obtained and stained with hematoxylin and eosin (H&E). The morphologic analysis was carried out in a blinded fashion.

Statistical Analyses
Results are presented as mean ± SEM. Unpaired t test was performed for statistical analyses of the presented data using SigmaPlot 5.0 software.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1 shows that DHA:BSA ameliorates ischemic renal injury. In these experiments, we clamped both left and right renal arteries for 20 min, and we gave intraperitoneal injections of either DHA:BSA or BSA alone at 4 h, 8 h, and 23 h after reperfusion. Scr was determined at 24 h (day 1), 72 h (day 3), and on day 7 after clamp release and the values of the DHA:BSA group were less than 50% of the BSA group. As shown in Figure 2, all of the BSA-treated controls had died by day 4; in contrast, more than 90% of the DHA: BSA-injected mice were still alive at day 7, when the experiment was stopped and the Scr had returned to less than 0.5 mg/dl. Morphologic examination (Figure 3) indicated less tubular injury in mice receiving DHA:BSA compared with BSA alone.



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  		Figure 1. DHA (all cis 4,7,10,13,16,19 docosahexaenoic acid C22: n-3) ameliorates ischemic renal injury. Both renal pedicles were clamped, and the mice received either 4 mg/kg body weight DHA as DHA:BSA complexes or BSA alone as described in Materials and Methods. There were initially 17 mice in the BSA group, and 15 mice in the DHA:BSA group. n = the number of surviving mice at a given time. P < 0.05 between DHA:BSA and BSA groups at days 1 and 3 after reperfusion by a t test.

 


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  		Figure 2. DHA improves survival after ischemic renal injury. Acute ischemic renal failure induced and DHA:BSA complexes or BSA given as in Figure 1. The survival on the y-axis is shown as percent of the number of mice in each group on day 0.

 


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  		Figure 3. DHA ameliorates ischemic renal injury. Acute ischemic renal failure induced and BSA (A) or DHA:BSA complexes (B) were given as in Figure 1. Kidneys harvested at 24-h reperfusion and stained with hematoxylin and eosin. Light photomicrographs compare injury in BSA-treated or DHA:BSA-treated mice. Glom and arrows indicate glomeruli. + medullary tubules; * cortical tubules that are severely injured in panel A and less severely injured in panel B. Magnification, x200.

 
We also performed two additional control experiments. First, we examined the effect of the BSA carrier for DHA. Twenty-four hours after renal ischemia, BSA- and saline-treated mice had similar Scr: 3.8 ± 0.1 mg/dl versus 3.1 ± 0.1 mg/dl, respectively (mean of five mice in each group ± standard error; P > 0.05). Second, we found that DHA:BSA did not affect the response of mice to uremia. Thus, after bilateral nephrectomies, the DHA:BSA- and BSA-treated mice had similar Scr: 3.3 ± 0.1 and 3.3 ± .2 mg/dl, respectively (mean of five mice per group ± standard error; P > 0.05).

Figure 4 shows that decreasing doses of DHA:BSA, from 4 to 2 mg DHA per kg body weight, were less effective at ameliorating ischemic injury. Doses of 1 mg/kg did not ameliorate renal injury. More than 4 mg of DHA/kg mouse was not more inhibitory.



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  		Figure 4. Renoprotective effect of DHA is dose-dependent. Bilateral renal pedicles were clamped, and DHA (as DHA:BSA complexes) or BSA were administered as in Figure 1. Scr was measured at 24 h after reperfusion. The molar ratio of DHA to BSA in the complexes was always 2. The serum creatinine is expressed as mg/dl. The P values shown compare the DHA groups and the BSA control by t test.

 
DHA had a greater ability to ameliorate ischemic renal injury than other fatty acids. Although arachidonic acid:BSA complexes also ameliorated injury, they were less effective than DHA. After 20 min of ischemia, the Scr was 2.7 ± 0.3 mg/dl, 1.7 ± 0.1, and 1.1 ± 0.2 in mice receiving BSA, 4 mg/kg of arachidonic acid:BSA, and DHA:BSA, respectively; P < 0.05 between the BSA and arachidonic acid, the BSA and DHA, and the arachidonic acid and DHA groups. This is consistent with a specific inhibitory effect of DHA, compared with other fatty acids, on fetal brain ischemia (29) and on activation of the iNOS and MHC Class II genes (25,26)

Figure 5 shows the effect of DHA on the mRNA abundance of selected cytokines after renal ischemia/reperfusion. The abundance of mRNA for IFN-{gamma}, IL-6, TNF-{alpha}, and TGF-{beta} was increased after renal reperfusion, and this increase was prevented by DHA. We found that the increase in IFN-{gamma} mRNA occurred in less than one third of seven experiments; any increase was prevented by DHA. The variability in detecting IFN-{gamma} mRNA may be due to the low levels present and is consistent with its reliable detection by RT-PCR (30,31) but not RNase protection assays (32). The increased IL-6 mRNA after ischemia/reperfusion was consistent but was prevented by DHA in only half of our experiments. This may reflect weak inhibition of this cytokine.



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  		Figure 5. The effect of DHA on cytokine mRNA abundance. Bilateral renal pedicles were clamped and DHA (as DHA:BSA complexes, 4 mg/kg mouse) or BSA were administered as in Figure 1. At 24 h, the Scr was measured and RNA was harvested for RNase protection assays. See Materials and Methods.

 
Table 1 summarizes the results of seven experiments; each experiment consisted of a control nonischemic kidney, an ischemic kidney from a BSA-treated mouse, and an ischemic kidney from a DHA:BSA-treated mouse. RNase protection assays for TNF-{alpha} and TGF-{beta} were performed on the kidneys. When the data for these seven experiments were considered together, the TNF-{alpha} mRNA abundance in ischemic BSA-treated kidneys increased by a factor of 3.4 ± 0.6 (mean ± SEM) over the nonischemic control; treatment with DHA:BSA decreased this factor to 1.1 ± 0.2 (mean ± SEM). By a t test, the P value was less than 0.01. In five experiments, the TGF-{beta} mRNA abundance in ischemic BSA-treated kidneys increased by a factor of 2.7 ± 0.1 (mean ± SEM) over the nonischemic control; treatment with DHA:BSA decreased this factor to 1.3 ± 0.1 (mean ± SEM). By a t test, the P value was less than 0.01. Altogether, Figure 5 and the seven different experiments of Table 1 show that renal ischemia increased the expression of TNF-{alpha} and TGF-{beta} and that this increase was prevented by DHA.


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  		Table 1. Densitometry of RNase protection assays for TNF-{alpha} and TGF-{beta}
 
As previously reported by others (see review, reference 14), we found that renal ischemia increased iNOS gene expression. Our new finding was that DHA prevented this increase; Figure 6 shows one representative RNase protection assay, and Table 2 summarizes the results of three different experiments. These three experiments involved four BSA-treated and four DHA:BSA-treated ischemic kidneys, as well as four control nonischemic kidneys. Each value shown in Table 1 represents an RNase protection assay on a single kidney from a mouse treated with either BSA or DHA;BSA. When the data for ischemic kidneys were considered together, the iNOS mRNA abundance in ischemic BSA-treated kidneys increased by a factor of 2.5 ± 0.2 (mean ± SEM) over the nonischemic control; treatment with DHA:BSA decreased this factor to 1.2 ± 0.1 (mean ± SEM). By a t test, the P value was less than 0.01. The point of Figure 6 and Table 2 is that renal ischemia increased the expression of iNOS and that this increase was prevented by DHA.



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  		Figure 6. DHA inhibits iNOS gene expression in the ischemic kidney. Bilateral renal pedicles were clamped, and DHA:BSA or BSA were administered as in Figure 1. At 24 h, the Scr was measured and RNA was harvested for RNase protection assays.

 

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  		Table 2. Densitometry of RNase protection assays for iNOS
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found that DHA ameliorated renal ischemic injury by both functional and histologic criteria. This was associated with decreased activation of the genes for TNF-{alpha}, TGF-{beta}, and iNOS.

As reviewed in the Introduction, inactivating TNF-{alpha} ameliorates ischemic ARF. In addition to the kidney, increased TNF-{alpha} is found in the blood and in tissue after ischemic injury to the heart (33–35), striated muscle (36,37), and brain (38). Injury is ameliorated by inactivating TNF-{alpha} with monoclonal anti–TNF-{alpha} antibodies or receptor antagonists (37–43). In addition, administration of exogenous TNF-{alpha} exacerbates the ischemic injury (44). Such receptor antagonists and antibodies may prevent TNF-{alpha} from activating endothelium and thus facilitating inflammation, and it may also prevent TNF-{alpha} from triggering apoptosis (see review, reference 45).

Although the observation that DHA inhibits TNF-{alpha} production by the ischemic kidney has not been reported previously, such inhibition would be consistent with the inhibitory effects of dietary DHA on monocyte TNF-{alpha} production reviewed in the Introduction. NF-{kappa}B may contribute to TNF-{alpha} gene transcription, and it is activated after renal ischemia (46). DHA inhibits activation of this transcription factor in other systems (27,47). Furthermore, this inhibitory effect on TNF-{alpha} may also help explain the beneficial effects of long-term DHA-containing diets on acute ischemic injury to various tissues (24,48,49). Although TNF-{alpha} production is also controlled at the translational step (50), decreasing mRNA abundance should ultimately inhibit production of this molecule.

In addition to decreasing TNF-{alpha} mRNA abundance, DHA also consistently prevented increases of TGF-{beta} mRNA after ischemia-reperfusion. Such increases after renal ischemia have been reported (51,52). Although regulation of TGF-{beta} is complex and includes many posttranslational steps (53), decreasing its mRNA abundance should ultimately decrease the amount of biologically active protein, because TGF-{beta} may contribute to renal fibrosis seen after severe injury, and its inhibition may also be beneficial.

As discussed in the Introduction, the iNOS gene is activated after renal ischemia and exacerbates injury. We found that DHA inhibited iNOS gene activation, and this may contribute to its salutary effect.

How DHA inhibits activation of the above three genes is the focus of ongoing experiments in our laboratory. Several possibilities must be explored. These include an inhibitory effect of DHA on IRF-1. The gene for this transcription factor is activated in stressed cells and cells stimulated by cytokines. This transcription factor contributes to activation of the genes for both iNOS (54) and TNF-{alpha} (55). We have previously demonstrated that DHA inhibits IRF-1 gene activation in macrophages stimulated by IFN-{gamma}, and the formation of "enhanceosomes" consisting of IRF-1 and NF-{kappa}B (27). If this inhibitory effect also occurs in the ischemic kidney, it would contribute to DHA’s inhibition of TNF-{alpha} and iNOS, and thus to DHA’s salutary effects.

Furthermore, DHA may interact directly with transcription factors that regulate renal injury as it does with transcription factors that regulate fatty oxidation and other metabolic pathways (see review, reference 56). Among the transcription factors known to bind to DHA are the peroxisome proliferator-activated receptors (PPAR) (56) and the retinoic acid X nuclear receptor (57). The interaction with PPAR may be potentially important because of these transcription factors’ role in regulating inflammation (58). Although the above data set a precedent for regulation of gene activation by DHA, the precise mechanisms for gene regulation, in particular TNF-{alpha} and iNOS, by DHA after renal ischemia remain to be determined. Finally, DHA interferes with the metabolism of arachidonic acid to eicosanoids. This may affect cell growth and inflammation (for example, reference 59).

Most previous studies of DHA have used an oral route, and prolonged administration was necessary to achieve therapeutic levels. Although useful for the treatment of chronic diseases, such as atherosclerosis, autoimmunity, or IgA glomerulonephritis (see reviews, references 60–62), such long-term oral therapy would not be helpful in the treatment of acute renal failure (24), which occurs acutely and often unexpectedly. Acute parenteral administration of nonesterified DHA may be complicated by the formation of fatty acid micelles, which are known to be toxic in vitro at concentrations above 10 µM (for example, references 63 and 64). We have overcome this difficulty by using DHA as DHA:BSA complexes, which are not toxic (25,26). Such DHA:protein complexes are found in the fetus and neonate, where serum concentrations of nonesterified DHA are 150 µM (65). In this report, we show that such DHA:BSA complexes ameliorate ischemic acute renal failure in the mouse and also inhibit ARF-associated increases in TNF-{alpha} and iNOS mRNA abundance. Given the known importance of these two genes in ischemic renal injury (see Introduction), their inhibition by DHA may contribute to its salutary effect.


   Acknowledgments
 
This work supported by grants from the American Heart Association, Welch Foundation, and the National Institutes of Health to Drs. Kielar, Jeyarajah, and Lu. We thank Deidra Reed and Bryan Wright for their technical assistance, and Ms. Kathy Trueman for creating the figures.


   Footnotes
 
Mariusz L. Kielar and D. Rohan Jeyarajah contributed equally to this project.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication November 5, 2001. Accepted for publication October 16, 2002.




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