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Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisana
ABSTRACT
This study was performed to examine the role of superoxide formation in the regulation of renal hemodynamic and excretory function and to assess its contribution in the pathogenesis of ANG II-dependent hypertension. Renal responses to acute intra-arterial infusion of the O2 scavenger tempol (50 μg?min1?100 g body wt1) with or without catalase (1,500 U?min1?100 g1; both native and polyethylene glycol-catalase), which reduces H2O2, were evaluated in anesthetized male Sprague-Dawley rats treated chronically with ANG II (65 ng/min) for 2 wk and compared with nontreated control rats. In ANG II-treated hypertensive rats, tempol caused increases in medullary (13 ± 2%), cortical (5 ± 2%), and total renal blood flow (9 ± 2%) without altering systemic arterial pressure. There were also increases in glomerular filtration rate (9 ± 2%), urine flow (17 ± 4%), and sodium excretion (26 ± 5%). However, tempol infusion in nontreated normotensive rats did not cause significant changes in any of these renal parameters. Coinfusion of catalase with tempol did not alter the responses observed with tempol alone, indicating that the observed renal responses to tempol in ANG II-treated rats were attributed to its O2 scavenging effects without the involvement of H2O2. Tempol infusion also significantly decreased 8-isoprostane excretion in ANG II-treated rats (39 ± 6%) without changes in H2O2 excretion. However, coinfusion of catalase reduced H2O2 excretion in both ANG II-treated (41 ± 6%) and nontreated rats (28 ± 5%). These data demonstrate that enhanced generation of O2 modulates renal hemodynamic and tubular reabsoptive function, possibly leading to sodium retention and thus contributing to the pathogenesis of ANG II-induced hypertension.
superoxide; angiotensin II
ANG II IS A powerful vasocontrictor and biological hypertensinogenic agent contributing importantly to the regulation of renal function and blood pressure (21, 27, 34). Chronic administration of a low dose of ANG II, which does not cause increases in blood pressure acutely, leads to the progressive development of hypertension (5, 9, 33) and an increase in oxidative stress (27, 34). Elevated intrarenal ANG II levels cause alterations in renal function, leading to sodium retention and thus contributing to the development and maintenance of hypertension (9, 33, 38). It has been proposed that the vasoconstrictor and hypertensive effects of ANG II are due, in part, to increases in the production of superoxide (O2) via activation of NADPH oxidase, which is an important enzymatic source of O2 in the body (2, 26).
As a highly reactive agent, O2 interacts with many endogenous substances, in particular with nitric oxide (NO), which acts as an antioxidant by reducing O2 levels (17). It is also degraded by superoxide dismutase (SOD) enzyme to form H2O2 (25). O2 oxidizes arachidonic acid nonenzymatically to generate free isoprostanes that are recognized as markers for increased endogenous O2 activity (6, 10, 17, 28). One of them, 8-isoprostane was demonstrated to be higher in both plasma and urine samples from hypertensive rats induced by ANG II (2, 28) or endothelin (31), as well as spontaneously hypertensive rats (SHR; see Ref. 30), compared with normotensive control rats. Generally, O2 is involved in cellular signaling in a variety of tissues under normal and in pathological conditions, where its inappropriate generation may contribute to the pathophysiology of hypertension. Recent reports support a direct renal vasoconstrictor and antinatriuretic effect of O2 in vivo (15, 16, 18) as well as an effect on sodium transport in vitro (23). These results suggest an integral role of O2 in regulation of kidney function in hypertension associated with elevated levels of ANG II.
In the present study, we examined the hypothesis that ANG II-induced O2 generation influences renal vascular and tubular function, leading to sodium retention, and thus plays a role in the pathogenesis of hypertension. We evaluated the renal functional responses to a O2 scavenger, tempol (4-hydroxy-tetramethylpiperidime-1-oxyl), infused directly in the left renal artery of anesthetized male Sprague-Dawley rats treated chronically with ANG II. Normal Sprague-Dawley rats served as control animals. Tempol is a low-molecular-weight nitroxide compound that is membrane permeable and that reduces endogenous O2 levels, as shown by many in vitro and in vivo studies (3, 15, 17, 18, 29). Because it has been suggested that administration of tempol may enhance the H2O2 level in the kidney (4, 19), we also evaluated the responses to coinfusion of catalase with tempol to delineate between the effects resulting from scavenging of O2 from those due to possible enhancement of H2O2 during administration of tempol. In these experiments, native catalase, which is poorly cell permeable, and the more cell-permeable polyethylene glycol (PEG) catalase were used to readily reduce H2O2 to water and thus minimize the action of H2O2 in the tissue (25). Intra-arterial administration of drugs was made directly in the kidney, allowing determination of their direct renal effects without alterations in blood pressure (12).
METHODS
Animal preparation. The study was performed in male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) in accordance with the guidelines and practices established by the Tulane University Animal Care and Use Committee. After 3 days acclimation, rats (220250 g) were randomly divided into nontreated groups and ANG II-treated groups. ANG II-treated rats were implanted with osmotic minipumps (model 2002; Alzet, Cupertino, CA) subcutaneously under anesthesia (pentobarbital sodium, 50 mg/kg ip; Sigma, St. Louis, MO). The osmotic minipumps were employed for chronic continuous infusion of a low dose of synthetic ANG II (Sigma) at a rate of 65 ng/min, which leads to the progressive development of hypertension during the course of 2 wk (2, 5, 34). In the present study, nontreated control groups were not implanted with the minipumps, since previous studies have reported that sham-operated (implanted minipump with saline) control rats do not show any differences in systemic and renal parameters compared with nonimplanted control groups (5, 36). Systolic blood pressure (SBP) was measured one time every 23 days by tail-cuff plethysmography to monitor blood pressure changes during a 2-wk period before acute experiments.
At the end of 2 wk of chronic ANG II treatment, acute clearance experiments were performed to determine renal responses to tempol and catalase in anesthetized (pentobarbital sodium, 50 mg/kg ip) ANG II-infused hypertensive and nontreated normotensive rats. The right jugular vein was catheterized for intravenous administration of solutions. The right femoral artery was cannulated to allow continuous monitoring of arterial blood pressure (AcqKnowledge data acquisition system; Biopac) and blood sampling. The left kidney was exposed via a flank incision and placed in a Lucite cup, and the ureter was cannulated with a PE-10 catheter for urine collection. A tapered PE-10 catheter was inserted in the renal artery via the left femoral artery to allow intra-arterial administration of drugs directly in the kidney (12). This catheter was kept patent by a continuous infusion of heparinized isotonic saline at a rate of 5 μl/min throughout the experiment.
An ultrasonic flow probe (Transonic System) was placed on the left renal artery to measure total renal blood flow (RBF). Laser-Doppler needle flow probes (500 μm OD; Periflex 4001; Perimed) were used to measure the relative changes in cortical (CBF) and medullary (MBF) blood flow, as reported earlier (5). Zero flow was determined when the renal artery was completely occluded at the end of the experiment.
Experimental protocol. Acute experiments were conducted in the following groups of rats: A) a nontreated normotensive group with 1) vehicle (saline) infusion (n = 8); 2) tempol infusion (n = 9); and 3) tempol + native catalase coinfusion (n = 6) or B) ANG II-treated hypertensive groups receiving 4) vehicle infusion (n = 9); 5) tempol infusion (n = 9); 6) tempol + native catalase coinfusion (n = 6); and 7) tempol + PEG-catalase coinfusion (n = 4).
After 60-min stabilization, the experimental protocol was started with a 30-min control clearance period to assess baseline control values of renal hemodynamic and excretory parameters. Next the intra-arterial infusion of tempol was given for 75 min to determine renal functional responses during drug administration. After the initiation of tempol infusion, an equilibration 15-min period was allowed before two 30-min clearance experimental periods in these experiments. Tempol (Sigma Chemical) was infused at a dose 50 μg?min1?100 g body wt1. This dose of tempol was selected based on findings in our earlier acute studies in dogs (17, 18) that showed significant reductions in urinary 8-isoprostane excretion rate (UIsoV; marker for endogenous O2 activity). Catalase (both native and PEG form; Sigma Chemical) was coinfused with tempol at a rate of 1500 U?min1?100 g body wt1 (11, 24). At the midpoint of the clearance collection period, an arterial blood sample was collected from the femoral arterial cannula to measure plasma inulin and sodium concentrations.
Urine volume was measured gravimetrically. Plasma and urine sodium and potassium concentrations were determined by flame photometry, and inulin concentrations were measured colorimetrically to determine glomerular filtration rate (GFR). Renal vascular resistance (RVR) and fractional sodium excretion (FENa) were calculated according to standard formulas. The enzyme immunoassay kit was used to measure urinary 8-isoprostane concentration (Assay Design, Ann Arbor, MI; see Refs. 17 and 18). Urinary H2O2 concentration was measured by colorimetric assay (Cayman Chemical, Ann Arbor, MI; see Refs. 13 and 18).
Data are expressed as means ± SE. Statistical comparisons between control and experimental values in the same group were conducted by paired Student's t-test. Statistical comparisons among the groups were conducted by two-way ANOVA for repeated measurements, followed by the Newman-Keuls test. P 0.05 was considered statistically significant.
RESULTS
Chronic infusion of a prolonged low dose of ANG II caused a slow progressive increase of SBP from 132 ± 7 to 188 ± 9 mmHg (n = 28; P < 0.001) during the 2-wk period of ANG II administration compared with normotensive nontreated rats in which SBP was not changed (134 ± 6 to 137 ± 7 mmHg; n = 23). These results are similar to those reported in previous studies (5, 33, 38).
In acute experiments in anesthetized animals, baseline values of mean arterial pressure (MAP), renal hemodynamics, and excretory parameters were assessed in all groups during the control period. Baseline MAP and RVR were significantly higher in ANG II-treated hypertensive rats and than in normotensive rats (156 ± 5 vs. 125 ± 2 mmHg and 25 ± 2 vs. 20 ± 1 mmHg?ml1?min?g, respectively). However, there were no significant differences in other renal parameters in either hypertensive or normotensive rats. Intra-arterial infusion of vehicle (saline) did not change MAP and renal function in either time control normotensive or hypertensive rats.
Renal hemodynamic and excretory responses to intra-arterial infusion of tempol. In normotensive rats, tempol infusion did not cause significant changes in RBF and RVR (Fig. 1). In contrast, tempol significantly increased RBF (9 ± 2%; P < 0.05) and decreased RVR (8 ± 1%; P < 0.05) in the ANG II-infused hypertensive groups (Fig. 1). As shown in Fig. 2, CBF and MBF were not changed significantly during infusion of tempol in normotensive rats. In hypertensive rats, tempol did not cause many changes in CBF [5 ± 2%; P = not significant (NS); Fig. 2A] but caused a significant increase in MBF (13 ± 2%; P < 0.05; Fig. 2B). As shown in Fig. 3A, GFR was not significantly altered by tempol in normotensive rats; however, it was significantly increased (9 ± 2%; P < 0.05) in the hypertensive rats during tempol infusion. Likewise, urine flow (V) responses to tempol were increased significantly (17 ± 4%; P < 0.05) only in the hypertensive rats but not in normotensive rats (Fig. 3B). Similar responses were also observed for sodium excretion (UNaV; Fig. 4). In normotensive rats, tempol did not significantly affect absolute or FENa. However, in hypertensive rats, there were significant increases in both UNaV (26 ± 5%; P < 0.05) and FENa (19 ± 4%; P < 0.05) during tempol infusion.
During administration of tempol in the renal artery, it was possible that some degree of spillover in the systemic circulation occurred. We did not measure other parameters, indicating extrarenal actions of tempol; however, there was minimal effect of intrarenal tempol administration on systemic arterial pressure either in normotensive control (126 ± 2 to 124 ± 3 mmHg; P = NS) or in ANG II-induced hypertensive (157 ± 5 to 152 ± 5 mmHg; P = NS) rats in the present study.
Renal hemodynamic and excretory responses to intra-arterial infusion of tempol + catalase. The observed renal responses to tempol infusion alone in both hypertensive and normotensive rats were not significantly altered by coadministration of catalase in these rats (Figs. 14). Renal hemodynamic and excretory responses to coinfusion of native catalase with tempol were similar to those observed during PEG-catalase with tempol in the experiments conducted in hypertensive rats. Table 1 provides the comparison of the responses to native catalase and PEG-catalase given with tempol in ANG II-induced hypertensive rats. These responses were not significantly different from each other; therefore, data were combined for the presentations in Figs. 15. In ANG II-infused rats, there were decreases in RVR (Fig. 1B) and increases in RBF (Fig. 1A), MBF (Fig. 2B), GFR (Fig. 3A), V (Fig. 3B), UNaV, and FENa (Fig. 4) during coadministration of tempol and catalase. CBF was not significantly increased in response to coadministration of tempol and catalase. MAP also remained unaltered during intra-arterial infusion of tempol + catalase in normotensive (123 ± 2 to 122 ± 2 mmHg; P = NS) and in hypertensive (154 ± 3 to 151 ± 2 mmHg; P = NS) animals.
Urinary excretion rate of 8-isoprostane and H2O2 responses to tempol and tempol + catalase coinfusion. As shown in Fig. 5A, basal control values of the UIsoV were significantly higher in hypertensive rats compared with normotensive rats. Tempol infusion decreased UIsoV significantly (39 ± 6%; P < 0.01) in hypertensive rats, and the similar reductions were observed during coinfusion of tempol and catalase in hypertensive rats. There were also decreases in UIsoV (24 ± 5%; P < 0.05) in normotensive rats during tempol administration; however, the magnitude was smaller than that in hypertensive rats. Basal control urinary H2O2 excretion rates (U V) were not different between normotensive and hypertensive groups of rats (Fig. 5B). In both hypertensive and normotensive rats, infusion of tempol alone did not cause any significant changes in U V. However, coinfusion of catalase with tempol led to significant decreases in U V in both hypertensive rats (41 ± 6%; P < 0.05) and normotensive rats (28 ± 5%; P < 0.05), as shown in Fig. 5B.
DISCUSSION
In this present investigation, we assessed renal hemodynamic and excretory responses to tempol, a O2 scavenging agent administered directly in the renal artery, in ANG II-induced hypertensive rats. Intra-arterial administration of tempol allowed us to evaluate its direct effect in the kidney without appreciable changes in blood pressure that are usually associated with systemic administration of tempol, as reported earlier (22, 29, 34). To our knowledge, no previous study except a recent investigation by Welch et al. (34) addressed this specific issue of determining the role of O2 in the modulation of renal function in ANG II-induced hypertension. However, the study of Welch et al. (34) used chronic treatment of tempol, which was associated with marked reduction in arterial pressure and thus complicated the proper assessment of direct O2 scavenging effects on renal function. In the present study, tempol was infused directly in the renal artery, which minimized its effects on systemic blood pressure and thus allowed more direct assessment of the responses to O2 scavenging on renal hemodynamics and excretory function. It was observed that acute administration of tempol caused significant increases in RBF, GFR, V, and UNaV in ANG II-induced hypertensive rats but not in normotensive control rats. Acute administration of tempol ameliorated the chronic ANG II-induced increases in UIsoV (marker for endogenous O2 activity; Fig. 5A), indicating that O2 activity is increased in these ANG II-treated rats, as reported previously (2, 28). Prolonged administration of tempol in ANG II-induced hypertensive rats was also shown to ameliorate the enhanced renal cortical NADPH oxidase activity as well as mRNA and protein expression for p22phox subunits of NADPH oxidase (34). Increases in RBF, GFR, and UNaV in response to tempol in ANG II-treated rats indicate that enhanced O2 production in these animals modulates renal function. An antinatriuretic effect of acute administration of ANG II was also shown to be partly mediated by concomitant generation of O2 (15, 18). Thus these present data indicate that ANG II-induced hypertension could be, at least in part, the result of the sodium-retaining effect of enhanced O2 activity.
It could be argued that a possible increase in intrarenal H2O2 concentration during tempol administration (4, 19) influenced the observed changes in renal function in this study. Although we did not measure the tissue level of H2O2 in the kidney, the present results demonstrate that U V was not altered during acute tempol administration in these rats. Previous studies also reported that tempol treatment acutely in dogs (18) or chronically in rats (13) did not alter U V. It was also shown that chronic tempol treatment did not alter U V in rats with normal salt intake but only in rats that were given a high-salt diet (35). However, in our earlier study (13), we have observed that high-salt intake alone in rats increased U V but not because of chronic administration of tempol. It is also known that as a modulatory agent, tempol can enhance heme proteins’ catalase-like activity, facilitating degradation of H2O2 (14). Supporting evidence from in vitro studies indicates that tempol decreased rather than increased H2O2 in renal proximal tubule cell cultures and moreover protected the cells against the cytotoxic effects of H2O2 (3, 8). Another point also needs to be considered that, although a modest change in renal medullary tissue concentration of H2O2 during tempol administration was reported earlier (4, 19), the effects of such changes in H2O2 on renal function are yet to be clearly defined. H2O2 was shown to act as a vasoconstrictor in renal medulla (4), but it has also been described as a vasodilator in renal cortical microcirculations (1). In the present study, cotreatment of catalase (both native and the PEG form) with tempol, although it caused significant reduction in U V, did not lead to any differences in the responses of renal hemodynamics and excretory function caused by tempol treatment alone. Thus the present findings do not support a significant involvement of H2O2 in the renal responses to tempol and implicate an involvement of O2 generation in the regulation of renal hemodynamics and excretory function in ANG II-induced hypertensive rats.
Tempol did not cause any significant alterations in the renal parameters in normotensive control rats (Figs. 14). This indicates that O2 activity remains minimal in these animals. Other studies have also demonstrated that systemic administration of tempol caused MAP reduction in ANG II-infused rats but had no significant effect in normotensive control animals (22, 34). Similar results were observed in Wistar-Kyoto rats compared with SHR (30). Although O2 is a constant product of cellular metabolism under normal conditions, its basal tissue concentration is kept to a minimal level because of efficient activity of endogenous antioxidant systems. Besides SOD and other antioxidative enzymes, endogenous NO is also known to exert a potent antioxidative effect (17). An appropriate physiological balance in oxidative status of the kidney during normal conditions is critically dependent on endogenous NO generation. As reported previously, chronic ANG II infusion significantly reduced extracellular SOD expression (2, 34); thus, the ability of enzymatic O2 degradation may be reduced in hypertensive compared with normotensive rats. Chronic administration of tempol ameliorated the suppressed extracellular SOD and moreover normalized enhanced NADPH oxidase activity in ANG II-induced hypertension (34). These findings indicate that the O2 level is increased in ANG II-infused hypertensive animals even though endothelial NO synthase activity may have increased in this model, as reported earlier (20).
In this study, the regional RBF responses to tempol infusion in ANG II-treated rats showed greater increases in MBF than in CBF; cumulatively, however, total RBF was increased. This indicates that concomitant generation of O2 during chronic ANG II infusion had a greater effect on medullary circulation than on cortical circulation. Previous studies to assess regional blood flow responses to tempol also suggest higher involvement of O2 in the renal medulla (7, 37). The diuretic and natriuretic effects of tempol in ANG II-infused hypertensive rats were modulated by increases in GFR and alterations of sodium reabsorption in the tubules. Because fractional excretion of sodium is significantly increased during tempol administration in ANG II-treated rats, it is also notable that enhanced O2 activity directly modulates tubular reabsorptive function as has been reported previously in in vitro (23) and in vivo studies (15, 16). O2 may exert its direct action in the kidney (14) or indirectly by reducing NO bioavailability (5, 17, 29), thus causing renal vasoconstriction and antinatriuresis. The observed renal responses to tempol in hypertensive rats could be due either to reduction of O2 activity, an increase in the bioavailability of NO, or both. In an earlier study in dogs (18), we observed that renal responses to acute administration of ANG II were ameliorated by tempol infusion both in intact conditions and under conditions of NO synthase inhibition. In isolated thick ascending limb preparations, tempol decreased NaCl absorption without increasing NO levels; that suggests the direct effect of O2-modulated NaCl absorption in thick ascending limb is independent of NO (23). Thus these results provide further evidence that an increase in O2 generation modulates renal hemodynamics and excretory function during chronic administration of ANG II.
Because it was reported that tempol exerts an inhibitory effect on sympathetic nerve activity (36), it could be argued that a neural factor was involved in the observed renal responses to tempol in the present study. However, it was also demonstrated that enhanced O2 activity by SOD inhibition caused stimulation of renal sympathetic activity, a response that was shown to be ameliorated by tempol (32), indicating that tempol-induced inhibition of sympathetic activity could be related to its ability to scavenge O2 in the neural tissue. In the present study, tempol infusion in the renal artery did not cause any changes in systemic arterial pressure in either normotensive or hypertensive rats, indicating a minimal neural involvement in the observed responses to tempol. Moreover, the renal artery was isolated from surrounding tissue by severing the visible renal nerve fibers; thus, the kidney was mostly denervated during these acute experiments. In our earlier studies, where a denervated kidney preparation was conducted in dogs, tempol was also shown to induce changes in renal function during treatment with ANG II and NO inhibition (17, 18). The vasodilator and natriuretic responses to tempol may indicate an involvement of natriuretic factors in these responses. However, marked changes in circulating factors, such as atrial natriuretic peptide induced by tempol administration, were not expected, since there was no indication of any changes in circulatory volume during tempol administration. Moreover, tempol did not cause any effects in normotensive rats; thus, a marked involvement of sympathetic activity and circulating natriuretic factors seems unlikely in the renal responses to tempol observed in the present study.
In conclusion, these data indicate that the generation of O2 due to ANG II administration modulates renal hemodynamic and excretory function, possibly leading to sodium retention and thus contributing to the development of ANG II-dependent hypertension.
GRANTS
This study was supported by National Heart, Lung, and Blood Institute Grants HL-51306 and HL-26371.
ACKNOWLEDGMENTS
We acknowledge the technical help provided by Dr. Mohammed Z. Haque (Tulane University, Health Sciences Center). We also thank Dr. Ludek Cervenka (Institute for Clinical and Experimental Medicine, Prague, Czech Republic) for providing help in scientific discussion in this study.
FOOTNOTES
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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