Hypothyroidism attenuates protein tyrosine nitration, oxidative stress and renal damage induced by ischemia and reperfusion: effect unrelated to antioxidant enzymes activities
© Tenorio-Velázquez et al; licensee BioMed Central Ltd. 2005
Received: 25 June 2005
Accepted: 07 November 2005
Published: 07 November 2005
It has been established that hypothyroidism protects rats against renal ischemia and reperfusion (IR) oxidative damage. However, it is not clear if hypothyroidism is able to prevent protein tyrosine nitration, an index of nitrosative stress, induced by IR or if antioxidant enzymes have involved in this protective effect. In this work it was explored if hypothyroidism is able to prevent the increase in nitrosative and oxidative stress induced by IR. In addition the activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase was studied. Control and thyroidectomized (HTX) rats were studied 24 h of reperfusion after 60 min ischemia.
Male Wistar rats weighing 380 ± 22 g were subjected to surgical thyroidectomy. Rats were studied 15 days after surgery. Euthyroid sham-operated rats were used as controls (CT). Both groups of rats underwent a right kidney nephrectomy and suffered a 60 min left renal ischemia with 24 h of reperfusion. Rats were divided in four groups: CT, HTX, IR and HTX+IR. Rats were sacrificed and samples of plasma and kidney were obtained. Blood urea nitrogen (BUN) and creatinine were measured in blood plasma. Kidney damage was evaluated by histological analysis. Oxidative stress was measured by immunohistochemical localization of protein carbonyls and 4-hydroxy-2-nonenal modified proteins. The protein carbonyl content was measured using antibodies against dinitrophenol (DNP)-modified proteins. Nitrosative stress was measured by immunohistochemical analysis of 3-nitrotyrosine modified proteins. The activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase was measured by spectrophotometric methods. Multiple comparisons were performed with ANOVA followed by Bonferroni t test.
The histological damage and the rise in plasma creatinine and BUN induced by IR were significantly lower in HTX+IR group. The increase in protein carbonyls and in 3-nitrotyrosine and 4-hydroxy-2-nonenal modified proteins was prevented in HTX+IR group. IR-induced decrease in renal antioxidant enzymes was essentially not prevented by HTX in HTX+IR group.
Hypothyroidism was able to prevent not only oxidative but also nitrosative stress induced by IR. In addition, the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase seem not to play a protective role in this experimental model.
Reactive oxygen species (ROS) [1, 2] and reactive nitrogen species such as peroxynitrite (ONOO-)  are involved in the damage induced by ischemia and reperfusion (IR). The damage by reactive nitrogen species has been made evident by the increase in protein tyrosine nitration [3–6]. The consequences of IR include alterations in DNA, lipids, and proteins (carbonyl formation and nitrosylation) [3–6]. Renal IR is associated with acute renal failure [3, 4] as well as proximal tubular damage [1–3]. IR-induced damage is ameliorated by spin traps , inhibition of inducible nitric oxide synthase , lecithinized superoxide dismutase (SOD) , ebselen, a ONOO- scavenger , inhibitors of calpain activation , SOD and catalase (CAT) mimetic , antioxidants [7, 8], or in the other circumstances such as hypothyroidism . Paller  found that the renal damage and the increase in malondialdehyde (MDA) induced by IR were significantly lower in hypothyroid than in euthyroid rats. The specific mechanisms involved in the protective effect of hypothyroidism against renal IR remain to be fully elucidated.
The role of antioxidant enzymes in the oxidative damage to kidney has been studied. It has been found that the elevated expression of antioxidant enzymes including CAT, SOD, glutathione peroxidase (GPx) [10–15], and more recently heme oxygenase-1 [16, 17], prior to renal oxidant insult, was able to ameliorate renal damage. Furthermore, the inhibition of CAT  or heme oxygenase-1  aggravates renal damage induced by puromycin aminonucleoside  or IR , respectively. These data strongly suggest that the modulation of the antioxidant enzymes may alter the renal damage induced by oxidants. It is unknown if the antioxidant enzymes may be regulated differentially and involved in the protective effect of hypothyroidism against renal IR. Interestingly, the administration of some exogenous antioxidants is able to modulate antioxidants enzymes and renal damage induced by IR [19–21]. In addition, (-)-epicatechin 3-O-gallate  and Wen-Pi-Tang  induced renal antioxidant enzymes and protected against lipopolysaccharide- and IR-induced kidney damage and plasma 3-nitrotyrosine (3-NT) formation. Tyrosine nitration may be induced not only by ONOO-, but also by another reactive nitrogen species including nitrogen dioxide radical (NO2 •) and dinitrogen trioxide (N2O3). ONOO- is a potent oxidation species that have been found to cause also lipid peroxidation and cytotoxicity [24–26].
Based on the above information, in the present paper we evaluated if hypothyroidism is able to prevent against the nitrosative stress induced by IR. Nitrosative stress was evaluated by measuring nitrated proteins by immunohistochemistry using antibodies against 3-NT [3–6, 27, 28]. Oxidative stress was evaluated using immunohistochemical techniques to evaluate the protein carbonyl content  and 4-hydroxy-2-nonenal (4-HNE) protein adducts [30, 31]. The protein carbonyl content was measured using antibodies against dinitrophenol (DNP)-modified proteins . In addition the activity of the antioxidant enzymes CAT, GPx, and SOD was studied before and after renal IR in control and hypothyroid rats.
Xanthine, nitroblue tetrazolium (NBT), 3,3-diaminobenzidine, bovine serum albumin, xanthine oxidase, NADPH, glutathione reductase (GR), 2,4-dinitrophenylhydrazine, and reduced glutathione (GSH) were purchased from Sigma (St. Louis, MO, USA). Ethylenediaminetetraacetic acid disodium salt (EDTA Na2), ammonium sulfate, and copper chloride were purchased from JT Baker (Mexico City, México). Hydrogen peroxide (H2O2), formaldehyde, and sodium carbonate were obtained from Mallinckrodt (Paris, KY, USA). Sodium azide was obtained from Merck (Mexico City, México). Rabbit anti-3-NT polyclonal antibodies were from Upstate (Catalogue # 06-284, Lake Placid, NY, USA). Goat anti-DNP polyclonal antibodies (Catalogue # J06) were from Biomeda Corporation (Foster City, CA, USA). Mouse anti-4-HNE monoclonal antibodies (Catalogue #24325) were from Oxis International Inc. (Portland, OR, USA). Anti-rabbit Ig horseradish peroxidase antibody (Catalogue # NA-934) and anti-mouse Ig horseradish peroxidase antibody (Catalogue # NIF-825) were purchased from Amersham Life Sciences (Buckinghamshire, England). Donkey anti-goat horseradish peroxidase antibodies (Catalogue # SC2020) were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA). All other chemicals were reagent grade and commercially available.
Induction of hypothyroidism
All animal procedures were approved by the Animal Care Committee of the Instituto Nacional de Cardiología "Ignacio Chavez" and followed the guidelines of Norma Oficial Mexicana (NOM-ECOL-087-1995). Male Wistar rats weighing 380 ± 17 g underwent surgical thyroidectomy with parathyroid reimplant (HTX), as previously described [32–35]. Briefly, the trachea was exposed under ether anesthesia, and under a stereoscopic microscope (Wild M5, Wild Heerbrugg, Switzerland), the parathyroid glands were visualized, dissected from the thyroid gland, and reimplanted into the surrounding neck muscles. The thyroid gland was then carefully dissected, to avoid injury to the laryngeal nerves, and completely excised. The effectiveness of this procedure was assessed by determining the concentration of calcium, phosphorous and thyroxine in 10 sham-operated control and 10 HTX rats, using standard techniques. The results obtained 15 days after surgery were: Ca2+ of 10.2 ± 3 in control vs. 10.3 ± 0.2 mM in HTX; phosphorous of 6.5 ± 0.3 in control vs. 6.3 ± 0.5 mM in HTX; and thyroxine of 6.4 ± 0.77 in control vs. 1.18 ± 0.19 μg dL-1 in HTX, P < 0.05. The sham group (375 ± 14 g) underwent a surgical procedure in which the animals were anesthetized, the trachea was exposed and then the incision was closed simulating the thyroidectomy surgery. The body weight for HTX and CT rats obtained 15 days after surgery was 389 ± 22 g and 417 ± 25 g, respectively.
Ischemia and reperfusion studies
Four groups of rats were studied: Control (CT), sham operated animals; hypothyroid (HTX), rats subjected to thyroidectomy; ischemia and reperfusion (IR), rats submitted to IR; and HTX+IR, rats subjected to HTX plus IR. The experimental protocol was performed 15 days after the thyroidectomy (HTX group) or the simulated surgery (CT). Under anesthesia and heparin administration, blood samples were obtained and the kidneys were reperfused and removed. Additional animals from CT and HTX groups were subjected to right nephrectomy and the left renal artery was occluded with a non-traumatic vascular clamp for 60 min. Then, the clamp was released allowing the reestablishment of renal blood flow or reperfusion and 24 h after the rats were anesthetized, blood samples were obtained and the kidney was washed with 0.9% saline solution and excised. These groups were named as IR and HTX+IR, respectively. Blood plasma was obtained and stored at -40°C. Kidney was used for histological and immunohistochemical studies and for determination of antioxidant enzymes activities. Areas of the kidney (renal cortex, outer medulla and inner medulla) were macroscopically dissected using a razor blade and frozen at -70°C for further measurement of enzymatic activities.
Determination of plasma creatinine and blood urea nitrogen (BUN)
Creatinine and BUN were measured using a creatinine analyzer model 2 and a BUN analyzer 2 (Beckman Instruments, Fullerton, CA, USA), respectively.
Kidney tissue slices were fixed in 10% neutral buffered formaldehyde solution, and embedded in paraffin [27, 36, 37]. Sections at 4 μm of thickness were obtained and stained with hematoxylin-eosin (H&E). Histologic assessment of tubular necrosis was determined semiquantitatively using a method described by Chatterjee et al. . The score was graded from 0 to 3 where 0 = normal histology, 1 = tubular cells swellings, brush border loss, nuclear condensation, with up to one third of tubular profile showing nuclear loss; 2 = same as for score, but greater than one third and less than two thirds of tubular profile shows nuclear loss; 3 = grater of two thirds of tubular profile shows nuclear loss. In addition a quantitative histological damage was determined by using a Leica Qwin Image Analyzer (Leica Microsystems, Cambridge, UK). The following parameters were quantified: (a) the percentage of tubules with hyaline casts in the renal cortex, using the low power magnification objective, three random choice fields were studied counting the tubules without and with hyaline casts to determine the percentage of the latter, and (b) in those tubules with hyaline casts, the total lumen area and the area occupied by the cast were determined, then the percentage of the lumen area occupied by the hyaline cast was determined.
Immunohistochemical localization of 3-NT, DNP, and 4-HNE
For immunohistochemistry, 4 μm sections were deparaffinized with xylene and rehydrated with ethanol. Endogenous peroxidase was quenched/inhibited with 4.5% H2O2 in methanol by incubation for 1.5 h at room temperature. The sections used for DNP immunohistochemistry were incubated with 0.2% dinitrophenylhydrazine in 2 N HCl for 60 min at room temperature in absence of light and then were extensively washed. Nonspecific adsorption was minimized by leaving the sections in 3% bovine serum albumin in phosphate buffer saline for 30 min. Sections were incubated overnight with 1:700 dilution of anti-3-NT antibody  or with 1:500 dilution of anti-DNP antibody or with 1:100 dilution of anti-4-HNE antibody . After extensive washing with phosphate buffer saline, the sections were incubated with 1:500 dilution of peroxidase conjugated anti-rabbit Ig antibody (for 3-NT) or with a 1:500 dilution of a peroxidase conjugated anti-goat Ig or anti-mouse IgG (for DNP and 4-HNE, respectively) for 1 h, and finally incubated with H2O2-diaminobenzidine for 1 min. Sections were counterstained with hematoxylin (for 3-NT and 4-HNE) or with methyl green (for DNP) and observed under light microscopy. All the sections from the four studied groups were incubated under the same conditions with the same antibodies concentration, and in the same running, so the immunostaining was comparable among the different experimental groups. Quantitative image analysis was performed with a Zeiss KS 300 Imaging System 3.0 (Carl Zeiss Vision GmbH, Hallbergmoos, Germany). This software determines densitometric means value of selected tissue regions. Thus, 10 fields/rat were randomly selected and the intensity of the 3-NT, 4-HNE, and DNP immunostaining was determined. We normalized the data (arbitrary units) to 1.0 using the control kidneys. We run negative controls omitting primary and/or secondary antibodies.
Renal cortex, outer medulla and inner medulla were homogenized in a Polytron (Model PT 2000, Brinkmann, Westbury, NY, USA) for 10 seconds in cold 50 mM potassium phosphate, 0.1% Triton X-100, pH = 7.0 . The homogenate was centrifuged at 19,000 × g and 4°C for 30 min and the supernatant was separated to measure total protein and the activities of CAT, GPx, and SOD. Total protein was measured by the method of Lowry et al. .
Renal CAT activity was assayed at 25°C by a method based on the disappearance of H2O2 from a solution containing 30 mM H2O2 in 10 mM potassium phosphate buffer pH 7.0 at 240 nm . The reaction was started by the addition of 25 μL of the sample to 725 μL of H2O2. Under the described conditions, the decomposition of H2O2 by CAT contained in the samples follows a first-order kinetic as given by the equation k = 2.3/t log Ao/A where k is the first-order reaction rate constant, t is the time over which the decrease of H2O2, due to CAT activity, was measured (15 s), and Ao/A is the optical density at times 0 and 15 s, respectively. The results were expressed in k/mg protein.
Glutathione peroxidase assay
Renal GPx activity was assayed by a method previously described . Reaction mixture consisted of 50 mM potassium phosphate pH = 7.0, 1 mM EDTA, 1 mM sodium azide, 0.2 mM NADPH, 1 U/mL of glutathione reductase, and 1 mM GSH. One hundred μL of the appropriate dilution of tissue homogenates were added to 0.8 mL of mixture and allowed to incubate for 5 min at room temperature before initiation of the reaction by the addition of 0.1 mL 2.5 mM H2O2 solution. Absorbance at 340 nm was recorded for 3 min and the activity was calculated from the slope of these lines as μmoles of NADPH oxidized per min taking into account that the millimolar absorption coefficient for NADPH is 6.22 mM-1cm-1. Blank reactions with homogenates replaced by distilled water were subtracted from each assay. The results were expressed as U/mg protein.
Superoxide dismutase assay
SOD activity in kidney homogenates was assayed by using a previously reported method . A competitive inhibition assay was performed using xanthine-xanthine oxidase system to reduce NBT. Mixture reaction contains in a final concentration: 0.122 mM EDTA, 30.6 μM NBT, 0.122 mM xanthine, 0.006% bovine serum albumin, and 49 mM sodium carbonate. Five hundred μL of tissue homogenate at the appropriate dilution, were added to 1.66 mL of the mixture described above, then 50 μL xanthine oxidase, in a final concentration of 2.8 U/L, were added and incubated in a water bath at 27°C for 30 min. The reaction was stopped with 066 mL of 0.8 mM cupric chloride and the optical density was read at 560 nm. One hundred percent of NBT reduction was obtained in a tube in which the sample was replaced by distilled water. The amount of protein that inhibited NBT reduction to 50% of maximum was defined as one unit of SOD activity. Results were expressed as U/mg protein.
The data are expressed as the mean ± SD. Data were analyzed with a non-paired t-test or with ANOVA followed by multiple comparisons by Bonferroni t test, as appropriate. P value less than 0.05 was considered statistically significant.
General and biochemical data
Plasma creatinine and BUN in the four groups of rats studied.
0.45 ± 0.05
0.40 ± 0.08
5.08 ± 0.55a
3.83 ± 0.41*
26 ± 2
23 ± 1
122 ± 11a
78 ± 17*
Histological and immunohistochemical analysis
Renal activity of antioxidant enzymes
Catalase activity (k/mg protein) in the four groups of rats studied.
0.22 ± 0.04 (16)
0.22 ± 0.02 (16)
0.17 ± 0.05a (5)
0.14 ± 0.04b (5)
0.07 ± 0.02 (16)
0.08 ± 0.02 (16)
0.08 ± 0.017 (7)
0.04 ± 0.004b,* (7)
0.013 ± 0.002 (16)
0.014 ± 0.003 (16)
0.012 ± 0.003 (7)
0.012 ± 0.002 (7)
Glutathione peroxidase activity (U/mg protein) in three sections of kidney from the four groups of rats studied.
0.10 ± 0.01 (16)
0.11 ± 0.01 (16)
0.07 ± 0.03a (7)
0.04 ± 0.01b,** (7)
0.07 ± 0.01 (16)
0.06 ± 0.01* (16)
0.03 ± 0.003a (7)
0.05 ± 0.007*** (7)
0.06 ± 0.02 (16)
0.05 ± 0.01 (16)
0.05 ± 0.02 (6)
0.03 ± 0.003 (6)
Superoxide dismutase activity (U/mg protein) in the four groups of rats studied.
13.3 ± 1.0 (16)
14.4 ± 1.0 (16)
15.1 ± 2.1 (7)
13.4 ± 3.2 (7)
10.9 ± 1.3 (16)
10.4 ± 1.1 (16)
8.2 ± 1.2a (8)
5.6 ± 1.5b,* (8)
Effect of experimental hypothyroidism on oxidative stress markers.
Change in oxidative stress markers
↔ MDA and ↑ GSH in renal cortex.
↑ Brain total antioxidant status.
↓ MDA and GSH levels in cerebral, hepatic and cardiac tissues.
↓ Advanced glycation end-products and MDA-lysine in liver.
↑ GSH and ↓ MDA levels in liver.
↑ MDA in plasma, erythrocytes, and liver tissue.
↔ MDA in kidney.
↔ GSH levels of kidney and liver.
↔ Brain TBARS.
↔ LPx and GSH, GSSG and GSSG/GSH ratio in skeletal muscle.
↓ TBARS in extensor digitorum longus muscle.
↔ TBARS in heart, liver, and soleus muscle.
↓ MDA and GSH in renal and testicular tissue.
In this study we also showed that IR damage was associated with an increase in tyrosine nitration which is consistent with previous studies [3–6]. Interestingly, it was observed that the protective effect of HTX was associated with a significant decrease in 3-NT immunostaining. Noiri et al. , Chatterjee et al. [4, 6], and Patel et al.  found that the protective effect of ebselen , PD150606 and E-64 (inhibitors of calpain activation) , interleukin-6 deficiency , and EUK-134 (a SOD and CAT mimetic)  in renal ischemia and reperfusion damage was associated with attenuation of nitrosative stress evaluated by tyrosine nitration. More recently it was shown that the protective effect of soy feeding of renal damage induced by puromycin aminonucleoside was associated with a decrease in tyrosine nitration .
Tyrosine nitration is induced by reactive nitrogen species including ONOO- which is synthesized by the reaction between superoxide anion (O2 •↓) and nitric oxide (NO•). The protective effect of ebselen, a ONOO- scavenger, in the IR-induced renal damage and tyrosine nitration suggests that ONOO- is enhanced and involved in tissue damage and nitrosative stress in this experimental model. There are evidences suggesting the increase of O2 •↓ and NO• in IR-induced renal damage [reviewed in ] which may favor ONOO- formation. In hypothyroid rats, the decreased nitrosative stress may be explained, at least in part, by the diminution in oxygen consumption and O2 •↓ production.
Effect of experimental hypothyroidism on antioxidant enzymes activities.
Change in antioxidant enzymes
↑ MnSOD and CAT and ↔ Cu, ZnSOD in brown adipose tissue.
In liver mitochondria:
↑ Total and Cu, ZnSOD, ↔ MnSOD, ↓ CAT.
↑ Total and Se-independent and Se-dependent GPx
↓ SOD and ↔ CAT in heart.
↑ GPx, ↔ CAT, and total SOD in heart.
↓ SOD and CAT and ↑ GPx in testis.
↑ Total and MnSOD, CAT, total and Se-dependent GPx.
↓ Se-independent GPx, and GR.
In cerebral cortex:
↑ Total SOD, Cu, ZnSOD, and GPx, and ↓ MnSOD.
↓ SOD, ↔ CAT, and ↑ GPx in kidney.
↓ Plasma GPx.
Cu, ZnSOD ↔ in extensor digitorum longus and soleus muscles, ↑ heart, and ↓ liver.
GPx ↔ in soleus muscle and liver ↑ extensor digitorum longus muscle and heart.
GPx ↑ in gastrocnemius muscle and heart, and ↔ in liver.
GR in ↔ heart, gastrocnemius muscle, and liver.
The most studied enzymes in hypothyroid animals are SOD, Cu, ZnSOD, MnSOD, CAT, GPx, and GR. The effect of hypothyroidism on the antioxidant enzymes in several tissues is not consistent (Table 6). In some cases the change of antioxidant enzyme activity seems to be tissue specific [47, 68]. On the other hand, within a single tissue, the response of the antioxidant enzymes to hypothyroidism is not always similar [55, 61–67].
Hypothyroidism attenuates not only renal but also cardiac damage induced by ischemia and reperfusion. Bobadilla et al.  have shown that hypothyroidism conferred protection against reperfusion arrhythmias and the cardiac release of creatine kinase and aspartate amino transferase and preserved the normal structure of myocardial tissue. In addition Chavez et al.  demonstrated that hypothyroidism renders mitochondria resistant to the opening of membrane permeability transition pore. This may be relevant to the protective effect of hypothyroidism in ischemia and reperfusion since it has been recognized that mitochondria play a key role in cell-death pathways by activating mitochondrial permeability transition pore and causing the release of cytochrome C and proapoptotic factors, as well as Ca2+ overload that promotes non-selective permeability of the inner membrane. The prolonged opening of the membrane permeability transition pore during the first few minutes of reperfusion is a critical determinant of cell death, and pharmacological inhibition of the pore at the time of reperfusion protects the cells .
It is concluded that HTX rats are more resistant to oxidative and nitrosative stress and renal damage induced by IR, which is not mediated by a differential regulation of the antioxidant enzymes CAT, GPx, and SOD.
List of abbreviations used
Analysis of variance
Blood urea nitrogen
Glutathione reduced form
Glutathione oxidized form
4-hydroxy-2-nonenal H&E Hematoxylin-eosin
Ischemia and reperfusion
- ONOO- :
Reactive oxygen species
This work was supported by CONACYT 0359P-M to M Franco.
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