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Division of Nephrology, Department of Medicine, and Department of Physiology, New York Medical College, Valhalla, New York 10595
Submitted 23 February 2004 ; accepted in final form 4 July 2004
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ABSTRACT |
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nitric oxide; oxygen radicals; renal physiology
Levels of oxidant stress are determined by the rates of oxygen radical production and scavenging. The discovery of homologs of the phagocyte NADPH oxidase that are expressed in blood vessels and organs such as the kidney has allowed further characterization and a better understanding of the sources of oxygen radicals other than white blood cells (8, 9, 19, 29). ANG II has been found to be a major stimulus for oxygen radical production via stimulation of these oxidases, defining another mechanism for its injurious effects (19, 23). Possibly of equal importance in the control of oxidant stress and nitric oxide bioavailability are oxygen radical scavenging mechanisms, such as the superoxide dismutases, which also play an important role in ameliorating hypertension (4, 17).
We have previously shown that there is impaired regulation of renal O2 consumption in SHR in response to stimulators of NO production (2). Experiments with the superoxide scavenger tempol suggested that increased superoxide levels lead to decreased NO bioavailability in these animals (2). Other studies have suggested vascular and renal oxidases as sources of enhanced oxidant stress in hypertension and other disease states (9, 19, 23). We hypothesized that the enhanced oxidant stress in these animals, leading to decreased NO and possibly potentiating hypertension, was due to enhanced oxygen radical production by the NAD(P)H oxidase complex or decreased scavenging of superoxide by endogenous systems. We also speculated that ANG II played a role in the development of oxidant stress. The studies presented here tested these possibilities in isolated kidney tissue from SHR.
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MATERIALS AND METHODS |
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Animals. Male SHR and Wistar-Kyoto rats (WKY) were purchased from Taconic Farms (Germantown, NY) at 10 wk of age and studied after 1 wk of acclimatization. Rats were maintained on a standard rat chow with 0.4% sodium content (Laboratory Rodent Diet, Richmond, IN) and allowed free access to food and water until the day of study. After death, the left kidneys were removed, decapsulated, and weighed. Tissue samples from the right kidney cortex were snap-frozen in liquid nitrogen and stored at –80°C for measurement of eNOS, SOD-1, -2, and -3, gp91phox, and Rac-1 levels (see below). The protocols used conform to the Guiding Principles for the Care and Use of Laboratory Animals of the American Physiological Society and the National Institutes of Health.
Preparation of kidney tissue slices and measurement of O2 consumption.
Thin slices of renal cortex (
1 mm, weight 10–20 mg) were prepared and incubated in Krebs bicarbonate solution containing (in mmol/l) 118 NaCl, 4.7 KCl, 1.5 CaCl 2, 25 NaHCO3, 1.2 KH2PO4, 1.1 MgSO4, and 5.6 glucose, pH 7.4, bubbled with 21% O2-5% CO2-74% N2 at 37°C for 2 h. At the end of incubation, each piece of tissue was placed in a stirred chamber with 3 ml of air-saturated Krebs bicarbonate solution containing 10 mmol/l HEPES and 5.6 mmol/l glucose (pH 7.4). The chamber was sealed with a Clark-type platinum O2 electrode (Yellow Springs Instruments, Yellow Springs, OH). O2 consumption was measured polarographically using an O2 monitor (model YSI 5300) connected to a linear chart recorder (model 1202, Barnstead/Thermolyne, Dubuque, IA). Dose-response curves of the effect of different agonists on kidney O2 consumption were then measured. Succinate (10–3 mol/l) and then sodium cyanide (10–3 mol/l) were added at the end of each experiment to confirm that changes in O2 consumption originated from mitochondrial respiration.
Renal cortical O2 consumption was calculated as the rate of decrease in O2 concentration, assuming an initial O2 concentration of 224 nmol/ml (calculated from O2 solubility at 37°C and 1 atm), and is expressed as nanomoles O2 consumed per minute per gram of tissue. O2 consumption due to the electrode is <5% of that observed in the presence of tissue. The effects of drugs used on O2 consumption are expressed as percent change from baseline O2 consumption. Baseline O2 consumption was measured in the cortex in the absence and presence of L-NAME (10–3 mol/l) in each group.
Effect of agonists of NO production on O2 consumption. Bradykinin or enalaprilat at concentrations of 10–7-10–4 mol/l was added in a cumulative concentration-dependent manner. They were used to measure the effects of stimulation of endogenous NO production on renal O2 uptake. The response to these drugs was also examined after preincubation with the NOS inhibitor L-NAME (10–3 mol/l) to verify the role of NO production by NOS in the regulation of O2 uptake. Each drug was assayed using tissue from six or seven rats in the presence or absence of L-NAME. Changes in O2 consumption in response to bradykinin and enalaprilat were also assessed in the presence of the superoxide dismutase mimetic tempol (10–3 mol/l), the ANG II type I receptor (AT1R)-antagonist losartan (10–6 mol/l), and the NAD(P)H oxidase inhibitor apocynin (10–5 mol/l) using tissue from SHR and WKY rats (n = 6 for each). In separate experiments, tissue from WKY rats was preincubated with ANG II (10–8 mol/l) before the addition of agonists and inhibitors (n = 6).
Effect of NO donor on O2 consumption. SNAP at concentrations of 10–7-10–4 mol/l was added in a cumulative concentration-dependent manner to assess the effects of exogenous NO on renal cortical O2 uptake. The response to SNAP was also examined after preincubation with L-NAME (10–3 mol/l). Each condition was tested in six or seven rats from each group.
Immunoblotting of proteins. Samples of renal cortex were pulverized in liquid nitrogen and homogenized in 5 vol of lysis buffer (0.05 M Tris·HCl, pH 7.2, 1 mM EDTA, 0.01 M dithiothreitol, 1 mg/ml PMSF, 100 µg/ml leupeptin, 100 µg/ml soybean trypsin inhibitor, and 20 µg/ml aprotinin, volume = 5x tissue weight) followed by sonication for 1 min at 4°C. Lysates were centrifuged at 10,000 g for 10 min at 4°C and stored at –80°C until use. Protein content of supernatants was measured using a Bio-Rad protein assay (Bio-Rad Laboratories).
Samples of tissue lysate (100 µg of protein) were loaded into individual lanes, subjected to electrophoresis on 8 or 15% polyacrylamide gels, and electrophoretically transferred from the gels to polyvinylidene difluoride membranes (Amersham Pharmacia Biotech) using a semidry transfer cell (Bio-Rad). After at least 1 h of blocking with 5% milk/PBS, membranes were incubated with antibodies to eNOS, SOD-1, SOD-2, SOD-3, gp91phox, or Rac-1 in 1% milk/PBS at 4°C overnight. After being washed, membranes were incubated with horseradish peroxidase-conjugated second antibodies to mouse, rabbit, or sheep IgG in 1% milk/PBS at room temperature for 2 h. Membranes were also probed with antibody to 
-actin (Novus Biologicals, Littleton, CO) to correct for differences in protein loading. Sites of antibody-antigen reaction were observed using Super Signal West Pico Chemiluminescent Substrate (Pierce, Rockford, IL) before exposure to X-ray film (Kodak, Rochester, NY).
The relative intensities of bands in autoradiograms were determined on an AlphaImager 2000 documentation and analysis system (Alpha Innotech, San Leandro, CA) followed by analysis using image software. Band intensity for each measured protein was divided by the intensity of the corresponding -actin band to correct for any differences in protein loading.
Statistical analysis. All data are expressed as means ± SE. Statistical analysis of baseline O2 consumption and densities of protein bands was performed using Student’s t-test. Changes in O2 consumption caused by drug treatment were analyzed using two-way ANOVA followed by multiple comparisons using the Tukey test (Sigma-Stat, SPSS-Science, Chicago, IL). Statistical significance was achieved at P < 0.05.
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RESULTS |
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Effect of bradykinin and enalaprilat on renal cortical O2 consumption. Cumulative doses of bradykinin (10–7-10–4 mol/l) produced significant, concentration-dependent decreases in renal cortical O2 consumption in WKY and SHR rats (WKY: from –1.3 ± 0.9 to –25.3 ± 2.3%, n = 6; SHR: from –0.3 ± 0.3 to –14.1 ± 1.2%, n = 7). The depression of renal cortical O2 consumption by bradykinin was significantly less in SHR than WKY rats (P < 0.05), confirming previous observations (2) (Fig. 1A). Similarly, the angiotensin-converting enzyme inhibitor enalaprilat (10–7-10–4 mol/l), which also stimulates endogenous NO production, caused concentration-dependent decreases in renal cortical O2 consumption in WKY and SHR rats (WKY: from –1.0 ± 0.6 to –25.6 ± 1.4%, n = 6; SHR: from 0 ± 0 to –15.5 ± 1.2%, n = 7), with a significantly lower effect in SHR than WKY rats (P < 0.05) (Fig. 1B), confirming previous observations. Addition of L-NAME significantly attenuated the effects of bradykinin and enalaprilat only in WKY rats, suggesting diminished production of NO by NOS in SHR (data not shown). The addition of tempol restored responsiveness to inhibition of O2 consumption in SHR to levels seen in WKY rats, confirming that destruction of NO by superoxide accounts for decreased NO bioavailability in SHR, as we have previously suggested (data not shown) (2).
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DISCUSSION |
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Enhanced production of superoxide has been demonstrated in numerous models of hypertension, including those due to partial nephrectomy, lead-induced hypertension, salt-sensitive hypertension, and the SHR (2, 14, 20, 21, 26–28, 35, 37). Evidence of enhanced oxidative stress has been obtained in humans with renovascular hypertension and appears to decrease after angioplasty (15, 22). Interestingly, patients with essential hypertension did not have enhanced excretion of a marker of in vivo lipid peroxidation despite a similar degree of hypertension (22). Segments of internal mammary artery and saphenous veins removed from patients undergoing coronary artery revascularization, most of whom were hypertensive, displayed NADH- and NAD(P)H-enhanced superoxide production, which was reversed by addition of apocynin or SOD (12). Suppression of superoxide production resulted in increased NO bioavailability and improved endothelium-mediated vasorelaxation via NO. Similarly, Guzik et al. (11) demonstrated superoxide production in all three vessel layers (adventitia, media, endothelium) but also noted that NO production scavenges superoxide, suggesting a much more complex interaction within the vessel wall.
Evidence that scavenging of NO by superoxide contributes to hypertension comes from experiments demonstrating increased NO bioavailability and decreased blood pressure after manipulations that decrease oxygen radical levels. Administration of superoxide scavengers ameliorates hypertension in SHR and salt-sensitive hypertension (21, 27, 28, 37). Production of superoxide in the renal cortex and medulla in Dahl salt-sensitive rats was decreased by tempol in association with a drop in blood pressure (21). Life-long supplementation with antioxidants also delays the onset of hypertension, as well as ameliorating its severity, in SHR (42), along with decreasing markers of oxidative stress. Directly decreasing production of superoxide with a highly specific inhibitor of vascular NAD(P)H oxidase decreases blood pressure in a mouse model of hypertension induced by ANG II infusion (24). Finally, scavenging of superoxide by SOD leads to decreases in blood pressure. This is demonstrated by significantly increased blood pressure in SOD-3-deficient mice with one clipped kidney or after infusion with ANG II compared with controls. (17). Infusion of recombinant SOD-3 into ANG II-treated mice rapidly lowered blood pressure (17). Transfection of SHR with the gene for human SOD-3 similarly lowered blood pressure (4). This was accompanied by improvement of acetylcholine-mediated vascular relaxation, suggesting increased availability of endothelium-generated NO.
There are several sources of increased superoxide production potentially implicated in vascular pathology, including xanthine oxidase, cytochrome P-450, uncoupled NOS, and the NAD(P)H oxidases (19). A kidney specific oxidase (Renox or NOX-4) has been described but is also found in vascular smooth muscle cells (8, 13, 29). Previous work in the SHR has documented overexpression of several components of the NAD(P)H oxidase complex through measurement of mRNA and/or protein levels by immunoblotting (3, 30, 42). Chabrashvili et al. (3) found expression of the p22phox, p47phox, and p67phox subunits of the NAD(P)H complex in the renal vasculature and elements of the distal tubule (starting at the thick ascending limb) in the kidney of SHR with significantly increased levels of p47- and p67phox in SHR compared with WKY animals. Zhan et al. (42) described increased levels of gp91phox, the catalytic subunit of the complex, and p22phox in the renal cortex of SHR. In the latter studies, the feeding of antioxidants not only reduced hypertension and oxidative stress but also decreased the level of expression of these subunits. Our work confirms overexpression of gp91phox and the small G protein Rac-1 that is necessary for activation of the oxidase. In thoracic aortas of SHR, increased levels of p22phox were also detected (30). Overexpression of these components, along with the beneficial effects of apocynin, an inhibitor of assembly of the complex, on the responsiveness of O2 consumption to stimulators of NO production, suggests that the NAD(P)H complex is an important source of oxygen radicals in SHR.
Another potential source of superoxide is uncoupled NOS. When levels of arginine or tetrahydrobiopterin (BH4) are low, NOS activation may favor production of superoxide rather than NO (32, 41). Evidence of enhanced oxygen radical production by NOS has been found in aortas from young, prehypertensive SHR (5), and administration of BH4 to SHR animals suppresses the development of hypertension as well as decreases superoxide production by aortic segments (16). Levels of NOS isoforms in the kidney have been reported to be elevated in SHR, including inducible NOS, neuronal NOS, and eNOS (33, 40). We have confirmed elevated eNOS expression in the renal cortex of SHR but have been unable to detect either inducible NOS or neuronal NOS in cortical samples. While we have not directly studied the possibility that uncoupled NOS in the renal cortex leads to the observed increase in oxidant stress, the ability of apocynin to completely reverse the defect seen in SHR suggests that NAD(P)H oxidase is the most important source of superoxide in the kidney.
The ability of the AT1R antagonist losartan to restore the effect of bradykinin and enalaprilat on the regulation of renal O2 consumption suggests a role of ANG II in mediating enhanced oxidant stress in SHR. This is further supported by the observation of induction of a similar defect in kidney from WKY rats by incubation with ANG II, a defect again reversed by superoxide scavenging with tempol or inhibition of NAD(P)H oxidase assembly with apocynin. ANG II is known to stimulate both activity and expression of NAD(P)H oxidase (9, 13, 19), which in turn reduces NO availability through scavenging. O2 utilization in the kidney of SHR for sodium transport has been shown to be less efficient than in WKY rats (38), an observation consistent with our finding of impaired regulation of renal O2 consumption in SHR and decreased NO bioavailability (2). This defect is largely reversed by the AT1R blocker candesartan in vivo (39), suggesting that activation of the AT1R mediates the increased O2 consumption. Our data further support a role in vitro for an AT1R-mediated increase in renal oxidant stress, leading to decreased NO bioavailability in the SHR.
Of interest, we also found that levels of extracellular SOD were reduced by 50% in SHR, potentially contributing further to oxidant stress in these animals. Studies in mice lacking either SOD-3 or Cu/Zn SOD (SOD-2) have suggested that deficiency of either of these enzymes can lead to increased superoxide levels and loss of NO, leading to decreased endothelium-mediated vasodilatation (6, 17), although basal blood pressure was not elevated in either group of deficient animals. Under stress, induced by clipping of one kidney or ANG II infusion, blood pressure was higher in SOD-3-deficient animals (17). Overexpression of human SOD-3 in SHR also leads to lowering of blood pressure (4), further supporting the importance of superoxide scavenging mechanisms in responding to oxidant stress. Another study of SOD expression in the aorta of SHR found increased levels of SOD-1 and SOD-2, whereas SOD-3 was not measured (30). These animals were, however, much older than the ones studied here, and these results might represent a change with aging or different regulation of SODs in the vessel wall vs. the kidney. Because expression of SOD-3 in mice is regulated by NO, the loss of SOD-3 in SHR may be a secondary, albeit aggravating, factor (7). In other models with enhanced oxidant stress, namely nephrectomy, salt loading, and lead-induced hypertension, renal expression of SOD-1 has been found to be decreased or increased, whereas SOD-2 was decreased or unchanged (18, 34, 36). Thus a general pattern of response of SOD expression in situations of oxidant stress is not apparent.
In summary, we have further confirmed the role of enhanced intrarenal superoxide production in limiting NO availability in the kidney in the SHR model of hypertension. We have demonstrated that enhanced expression and activation of elements of the NAD(P)H complex occur in these animals, contributing to oxidant stress, along with loss of an important counterregulatory element, SOD-3. Loss of NO occurs despite enhanced expression of eNOS, which in itself could be a response to lower levels of NO. Finally, an important role of stimulation of the AT1R by ANG II in the enhanced oxidant stress that occurs in these animals has been demonstrated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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. Hypertension 33: 424–428, 1999.This article has been cited by other articles:
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) and spontaneously hypertensive rats (SHR; 
). Both drugs caused significant dose-dependent decreases in O2 consumption that were significantly less in SHR. *P < 0.05 vs. WKY rats.
) but restored responsiveness in SHR (
). *P < 0.05 vs. SHR with apocynin.
), or N-nitro-L-arginine methyl ester (L-NAME; 
) all restored responsiveness to bradykinin compared with addition of ANG II alone (