Loss of Biphasic Effect on Na/K-ATPase Activity by Angiotensin II Involves Defective Angiotensin Type 1 Receptor-Nitric Oxide Signaling
Oxidative stress causes changes in angiotensin (Ang) type 1 receptor (AT1R) function, which contributes to hypertension. Ang II affects blood pressure via maintenance of sodium homeostasis by regulating renal Na+ absorption through its effects on Na/K-ATPase (NKA). At low concentrations, Ang II stimulates NKA; higher concentrations inhibit the enzyme. We examined the effect of oxidative stress on renal AT1R function involved in biphasic regulation of NKA. Male Sprague-Dawley rats received tap water (control) and 30 mmol/L of l-buthionine sulfoximine (BSO), an oxidant, with and without 1 mmol/L of Tempol (antioxidant) for 2 weeks. BSO-treated rats exhibited increased oxidative stress, AT1R upregulation, and hypertension. In proximal tubules from control rats, Ang II exerted a biphasic effect on NKA activity, causing stimulation of the enzyme at picomolar and inhibition at micromolar concentrations. However, in BSO-treated rats, Ang II caused stimulation of NKA at both of the concentrations. The effect of Ang II was abolished by the AT1R antagonist candesartan and the mitogen-activated protein kinase inhibitor UO126, whereas the Ang type 2 receptor antagonist PD-123319 and NO synthase inhibitor NG-nitro-l-arginine methyl ester had no effect. The inhibitory effect of Ang II was sensitive to candesartan and NG-nitro-l-arginine methyl ester, whereas PD-123319 and UO126 had no effect. In BSO-treated rats, Ang II showed exaggerated stimulation of NKA, mitogen-activated protein kinase, proline-rich-tyrosine kinase 2, and NADPH oxidase but failed to activate NO signaling. Tempol reduced oxidative stress, normalized AT1R signaling, unmasked the biphasic effect on NKA, and reduced blood pressure in BSO-treated rats. In conclusion, oxidative stress-mediated AT1R upregulation caused a loss of NKA biphasic response and hypertension. Tempol normalized AT1R signaling and blood pressure.
Angiotensin (Ang) II plays an important role in the regulation of body fluid and sodium balance through the modulation of renal tubular functions.1,2 In particular, Ang II acting via the Ang type 1 receptor (AT1R) stimulates the net sodium reabsorption in the renal proximal tubules, and an exaggerated effect of Ang II on this process contributes to the development of hypertension.1,2 In this regard, the ability of Ang II to stimulate Na/K-ATPase (NKA) activity in the renal proximal tubules is an important regulatory component of sodium absorption.3 It is recognized that Ang II exerts a biphasic effect on sodium transport in the kidney.4 Harris and Young5 have shown that Ang II added into peritubular fluid stimulates sodium and water absorption from rat proximal tubules at low (picomolar to nanomolar) concentrations and inhibits at high (nanomolar to micromolar) concentrations. Subsequent studies confirmed this unique biphasic sodium regulation by Ang II in different experimental conditions.6 These studies are particularly relevant because Ang II is generally reported to work as a stimulator of proximal tubular sodium transport; however, in situ proximal tubular fluid is reported to contain markedly high concentrations of Ang II.7 Therefore, inhibition by high concentrations of Ang II could also have some physiological relevance to the regulation of proximal tubular functions in vivo.
The biphasic effects of Ang II on sodium absorption are, at least in part, contributed by NKA regulation.6 The mechanism behind the biphasic effect of Ang II on the NKA is unclear; however, the stimulation by Ang II has been traditionally attributed to the activation of protein kinase C and/or the decrease in the intracellular cAMP level.6,8 It has been shown that Ang II, via AT1R, activates NO signaling in renal proximal tubules.9,10 We and others have reported that NO and sodium nitroprusside can decrease the NKA activity in proximal tubules and cultured opossum kidney cells.11,12 Because NO and Ang II are known to antagonize each other at many physiological functions, such as vascular relaxation, tubuloglomerular feedback, sodium absorption, and blood pressure (BP) regulation,9 it is possible that NO signaling may be a physiological modulator for Ang II-mediated NKA regulation.
Compelling experimental evidence indicates that oxidative stress plays an important role in AT1R signaling. It has been shown that, in experimental models of hypertension, the increase in oxidative stress coexists with AT1R upregulation.13,14 Conversely, Ang II via AT1R can activate NADPH oxidase and increase the production of superoxide (O2•−).15 On the other hand, the increased oxidative stress is associated with NO bioinactivation, because the reaction of O2•− with NO causes generation of peroxynitrite.16 Taken together, these data indicate that, whereas oxidative stress can positively modulate Ang II signaling via AT1R, it can also disrupt the function of its physiological antagonist NO and, thus, exaggerate AT1R signal transduction. Therefore, the purpose of this study was to examine the effect of oxidative stress on biphasic regulation of NKA activity by Ang II in renal proximal tubules with particular emphasis on the role of NO signaling.
Male Sprague-Dawley rats (Harlan, Indianapolis, Ind) were fed a normal rat diet and divided into following 4 groups: control (C), animals that were maintained on tap water; l-buthionine sulfoximine (BSO), animals that were provided with 30 mmol/L of BSO (Sigma); Tempol (T), animals that were provided with 1 mmol/L of Tempol (Sigma); and BSO+T, animals that were provided with BSO plus Tempol. All of the experiments were performed in compliance with Institutional Animal Care and Use Committee-approved protocol.
Preparation of Renal Proximal Tubular Suspension
Renal proximal tubular suspension was prepared as described previously.11 Experiments were performed with freshly prepared proximal tubules, and protein was determined by bicinchoninic acid method (Pierce).
Indices of Oxidative Stress
Production of malondialdehyde and O2•− was determined as described previously.11 Superoxide dismutase activity, nitrotyrosine, and 8-isoprostane were determined by commercially available kits.
NKA, Na/H-Exchanger 3, and Mitogen-Activated Protein Kinase Assay
NKA, Na/H-exchanger 3 (NHE3), and mitogen-activated protein (MAP) kinase were determined by routine laboratory procedures (please see the data supplement available at http://hyper.ahajournals.org).
Differences between means were evaluated using the unpaired Student t test or ANOVA with Newman-Keul’s multiple test, as appropriate. P<0.05 was considered statistically significant.
Oxidative Stress and BP
Treatment of Sprague-Dawley rats with BSO, Tempol, and BSO plus Tempol for 2 weeks had no effect on body weight and food intake (Table). Glomerular filtration rate was also similar among all of the experimental groups (Table). Compared with control, rats treated with BSO exhibited a significant increase in BP, plasma, and urinary 8-isoprostane levels; renal malondialdehyde; and nitrotyrosine content (Table). These rats also had decreased levels of renal glutathione and superoxide dismutase activity (Table). Tempol supplementation reduced oxidative stress and BP in BSO-treated rats. There were no significant differences in BP or oxidative/antioxidative markers between control and rats treated with Tempol alone (Table).
AT1R Expression in Renal Proximal Tubules
BSO treatment caused a significant increase in AT1R number (C: 301.2±29.8, BSO: 535.1±49.6, T: 330.6±30.2, and BSO+T: 382.3±39.1 fmol/mg of protein) and protein content (Figure S1A). Supplementation of Tempol normalized AT1R expression in BSO-treated rats (Figure S1A). Western blot showed a single protein band of ≈42 kDa in proximal tubules from control rats, which was markedly reduced by an AT1R-selective blocking peptide (Figure S1B). Equal protein loading was confirmed by stripping and reprobing the membranes with GAPDH antibodies, which showed similar band intensity in both lane 1 and lane 2 (Figure S1B).
Effect of Ang II on NKA and NHE3 Activity
Incubation of renal proximal tubules from control rats with Ang II produced a biphasic response of NKA, stimulation at picomolar concentration, and inhibition at micromolar concentration (Figure 1). However, the biphasic response of NKA to peptide was lost in rats treated with BSO (Figure 1). In BSO-treated rats, Ang II caused a concentration-dependent stimulation of NKA activity, which reached a plateau at 10−11 mol/L Ang II and remained unchanged through micromolar peptide concentrations (Figure 1). Ang II-mediated NKA stimulation was significantly higher in BSO-treated rats compared with control (Figures 1, S2A, and S2B). In addition, Ang II also caused significantly higher stimulation of NHE3 in BSO-treated rats compared with other experimental groups (Figure S2C). Tempol supplementation of BSO-treated rats normalized the Ang II-induced NKA and NHE3 overstimulation and restored the biphasic response of NKA (Figures 1 and S2A through S2C). The basal activities of NKA (nmol Pi/μg of protein per hour) and NHE3 (nmol 22Na+/mg of protein per minute) were similar in all 4 of the groups: NKA: C, 13.6±0.8; BSO, 14.3±0.9; T, 12.9±0.7; BSO+T, 14.4±1.1; NHE3: C, 4.3±0.2; BSO, 4.6±0.3; T, 4.1±0.4; BSO+T, 4.5±0.3. The immunoreactivity of NKA-α1 subunit and NHE3 was also similar in all of the experimental groups (Figure S2D and S2E).
Role of AT1R on NKA Activity
Incubation of proximal tubules with AT1R antagonist candesartan (1 μmol/L) blocked the Ang II-mediated NKA biphasic response in control (Figure 2A), Tempol, and BSO plus Tempol-treated (data not shown) rats. Candesartan also blocked the NKA stimulation induced by high or low Ang II concentrations in BSO-treated rats (Figure 2B). Ang type 2 receptor antagonist PD-123319 (1 μmol/L) failed to show any effect on NKA regulation in response to Ang II. These concentrations of candesartan and PD-123319 had no effect on basal NKA activity (basal: 13.9±0.4; candesartan: 13.6±0.5; PD-123319: 14.2±0.6 nmol Pi/mg of protein per hour).
We tested various inhibitors to investigate the pathway involved in Ang II-mediated NKA regulation. The MAP kinase inhibitor UO126 (10 μmol/L) antagonized the stimulatory effect of Ang II in both control and BSO-treated rats (Figure 2C and 2D) but did not alter the inhibitory effect of 10−6 mol/L Ang II in control rats (Figure 2C). NHE3 inhibitor amiloride (10 μmol/L) had no effect on either stimulatory or inhibitory response of peptide on NKA activity in control or BSO-treated rats (Figure 2C and 2D). The NO synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 1 mmol/L) or the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 50 μmol/L) had no effect on 10 pM Ang II-induced NKA stimulation in control and BSO-treated rats or 1 μmol/L of Ang II-mediated NKA stimulation in BSO-treated rats (Figure 2E and 2F). However, both l-NAME and ODQ abolished the inhibitory effect of Ang II (10−6 mol/L) on NKA in control rats (Figure 2E). These pharmacological compounds showed similar effects in Tempol and Tempol plus BSO-treated rats, as seen in control rats (data not shown), and did not alter the basal NKA activity (UO126: 13.2±0.6; amiloride: 14.0±0.3; l-NAME: 14.3±0.5; ODQ: 13.8±0.3 nmol Pi/mg of protein per hour).
Ang II-Mediated MAP Kinase Activation
We analyzed the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in renal proximal tubules. The Western blotting experiments showed that 10 pM (Figure 3) and 1 μmol/L (data not shown) of Ang II caused a significant increase in ERK1/2 phosphorylation, without affecting the ERK1/2 protein expression, in renal proximal tubules from both control and BSO-treated rats (Figure 3). However, the Ang II-mediated phosphorylation of ERK1/2 was markedly higher in BSO-treated rats compared with control rats (Figure 3). Tempol abolished the increased phosphorylation of ERK1/2 in BSO-treated rats, while showing no effect when provided alone (Figure 3). The Ang II (10 pM)-mediated ERK1/2 activation in control rats was blocked by candesartan and UO126, a MAP kinase inhibitor, whereas PD-123319 had no effect (Figure S3).
Ang II-Mediated NO and cGMP Accumulation
Incubation of proximal tubules with 10 pM Ang II failed to increase NO or cGMP levels in all of the experimental groups (data not shown). However, at micromolar concentration, Ang II caused significant a increase in L-[14C]citrulline accumulation in control rats but not in BSO-treated rats (Figure 4). The L-[14C]citrulline production was inhibited by l-NAME and candesartan but not by PD-123319 (Figure S4A). Similarly, Ang II (1 μmol/L) caused a significant increase in nitrate/nitrite production in control rats but had no effect in BSO-treated rats (Figure S4B). The nitrate/nitrite production was also sensitive to candesartan and l-NAME (Figure S4C). Interestingly, at similar concentrations, Ang II (1 μmol/L) caused significant cGMP accumulation in control rats but not in BSO-treated rats (Figure S4D). Preincubation of proximal tubules with candesartan, l-NAME, or ODQ inhibited the Ang II-mediated cGMP accumulation, whereas PD-123319 had no effect (Figure S4E). Tempol supplementation of BSO-treated rats restored the NO and cGMP production in response to high Ang II (1 μmol/L) concentration (Figures 4, S4B, and S4D). The basal NO (data not shown) and cGMP levels were similar in all of the experimental groups (C: 0.72±0.08; BSO: 0.67±0.07; T: 0.78±0.09; BSO+T: 0.70±0.06 pmol/mg of protein).
Ang II-Mediated O2•− Production
Incubation of tubular homogenates, from Ang II-exposed proximal tubules, with NADPH oxidase substrate reduced nicotinamide-adenine dinucleotide (0.1 mmol/L) caused an increase in O2•− production in all of the experimental groups (Figure 5A). However, the generation of O2•− in response to Ang II and in the presence of reduced nicotinamide-adenine dinucleotide was significantly higher in BSO-treated rats compared with control, Tempol, or BSO plus Tempol-treated rats (Figure 5A). In proximal tubules from control rats, the O2•− production was inhibited by candesartan and NADPH oxidase inhibitor diphenylene iodonium chloride (0.1 mmol/L), whereas PD-123319 had no effect (Figure S5A).
Incubation of homogenates, after the exposure of tubules to Ang II, with NOS substrate l-arginine (1 mmol/L) failed to produce O2•− in control, Tempol, or BSO plus Tempol-treated rats but caused significant O2•− production in BSO-treated rats (Figure 5B). The O2•− production in BSO-treated rats was sensitive to the NOS inhibitor l-NAME (1 mmol/L; Figure S5B). The Western blotting exhibited a significant increase in NADPH oxidase p22 subunit expression in BSO-treated rats compared with other groups, whereas there was no significant difference in the expression of the NADPH oxidase gp91phox subunit among the experimental groups (Figure S5C and S5D).
Ang II-Induced Proline-Rich Tyrosine Kinase 2 Activation
As illustrated in Figure 6, incubation of proximal tubules with Ang II caused a significant increase in proline-rich tyrosine kinase 2 (PyK2) phosphorylation in both control and BSO-treated rats. The Ang II-mediated PyK2 phosphorylation was higher in BSO-treated rats compared with control (Figure 6). Tempol normalized the Ang II-induced PyK2 phosphorylation in BSO-treated rats, while having no effect when given alone (Figure 6). The phosphorylation of PyK2 in response to peptide was blocked by candesartan and not by PD-123319 (Figure S6). PyK2 basal protein levels were similar in all of the groups (data not shown) and remained unchanged by Ang II exposure (Figure 6).
The results of this study show that, in Sprague-Dawley rats, oxidative stress increased BP, which was associated with renal AT1R upregulation and exaggerated signaling. In BSO-treated rats, Ang II caused significantly higher NKA stimulation and failed to cause inhibition of NKA activity, as seen in control rats. Our data shows that AT1R-mediated NKA stimulation by low Ang II concentration involves MAP kinase, whereas the inhibition at high Ang II concentration involves NO-cGMP signaling. Interestingly, whereas picomolar concentration of Ang II showed robust stimulation of MAP kinase in BSO-treated rats, it failed to activate NO-cGMP signaling and inhibit NKA activity at micromolar concentrations. In control rats, Ang II stimulated NADPH oxidase, but the activation of this enzyme was much higher in BSO-treated rats. In addition, Ang II-mediated, AT1R-dependent O2•− production was also contributed by NOS in BSO-treated rats. Furthermore, Ang II-mediated Pyk2 stimulation was also higher in BSO-treated rats compared with control animals. Supplementation of BSO-treated rats with Tempol abolished the oxidative stress, normalized AT1R expression and signaling, and reduced BP.
Oxidative stress contributes, at least in part, to the development and maintenance of hypertension, and antioxidant treatment lowers BP in hypertensive animal models.11,17–19 Also, AT1Rs are upregulated in central and peripheral sites involved in BP regulation in hypertension.13,14 Our results are consistent with these finding regarding the increased oxidative stress and AT1R function in hypertension. We found that BSO-treated rats exhibited high BP and showed marked oxidative stress and AT1R upregulation. Antioxidant supplementation restored redox status and normalized AT1R expression and BP. Although we did not elucidate the mechanisms for AT1R upregulation, evidence to date indicates that the AT1R gene possess the binding sites for nuclear factor κB (NF-κB).20,21 Cowling et al20,21 have shown that NF-κB activation is necessary for cytokine-induced AT1 mRNA upregulation in cardiac fibroblasts. NF-κB-dependent reporter constructs demonstrated rapid activation of NF-κB with interleukin 1β, which was paralleled by increased AT1R mRNA levels.20,21 Recently, we showed that oxidative stress caused increased nuclear translocation of NF-κB in BSO-treated rats.22 These data suggest that oxidative stress via NF-κB activation upregulates AT1R and contributes to the development of hypertension, thus elucidating the existence of novel cross-talk between oxidative stress and AT1R function in hypertension.
Ang II, via AT1R, stimulates net sodium absorption in renal proximal tubules and, thus, affects the BP regulation.23,24 Interestingly, Ang II exerts a biphasic regulation of NKA in proximal tubules.6,25 At picomolar concentrations, Ang II activates NKA, whereas at higher concentration an inhibitory effect is observed.6 We also found a biphasic response of Ang II on NKA activity in control rats. In BSO-treated rats the stimulatory response to NKA at picomolar Ang II was markedly higher than in control rats, but there was no inhibitory effect at higher concentrations. Tempol restored the biphasic Ang II response on NKA in BSO-treated rats. Physiologically, Ang II maintains body sodium and fluid balance and BP homeostasis by stimulating tubular sodium and fluid reabsorption. However, sustained increases in intrarenal Ang II levels because of local formation and/or uptake of circulating Ang II by proximal tubules may contribute to sodium retention and hypertension if sodium transporter stimulation is maintained at higher concentrations. Therefore, the lack of NKA biphasic response may contribute to increased sodium reabsorption and hypertension in BSO-treated rats.
Ang II is coupled to a variety of signaling cascades depending on the cell type, and both stimulatory and inhibitory roles of ERK have been suggested in the regulation of proximal tubular transport of sodium by Ang II.26 Also, conflicting data have been reported as to the identity of the receptor subtype involved in mediating biphasic response of Ang II. Some studies suggest the involvement of AT1R in stimulation and Ang type 2 receptor in inhibition.27 Our study indicates that, in normotensive rats, the biphasic peptide response on renal NKA is mediated by AT1 and not by Ang type 2 receptor subtype. With regard to MAP kinase pathways, the role of EKR1/2 activation in Ang II-mediated NKA was assessed using UO126. This inhibitor blocked the stimulatory effect of Ang II, while having no effect on inhibitory response in control rats. However, in BSO-treated rats, which lack the inhibitory response at higher Ang II concentration, UO126 blocked the NKA stimulation at both low and high concentration. These data suggest that, in renal proximal tubules, the Ang II-mediated NKA stimulation involves MAP kinase pathways and is independent of Ang II concentration.
The role of NO-cGMP signaling in Ang II-mediated NKA was assessed using NOS and soluble guanylyl cyclase inhibitors l-NAME and ODQ, respectively. Treatment of proximal tubules from control rats with l-NAME or ODQ abolished the inhibitory effect of Ang II while having no effect on stimulation of NKA in response to the peptide. Because NKA from BSO-treated rats lacks the biphasic response to Ang II, l-NAME or ODQ failed to show any effect on Ang II-mediated stimulation at both lower and higher peptide concentrations. The effect of Ang II on NO signaling was further investigated by examining the NO production and cGMP accumulation in response to Ang II. Interestingly, the incubation of proximal tubules from control rats with 1 μmol/L of Ang II caused a significant increase in NO and cGMP levels but failed to show response in BSO-treated rats. The Ang II-mediated NO and cGMP production in control rats was inhibited by l-NAME and candesartan, whereas PD-123319 had no effect. Tempol was able to restore the Ang II-mediated NO signaling, as well as the biphasic response of NKA in BSO-treated rats. These data confirm that the inhibitory response of NKA by Ang II is mediated by NO-cGMP signaling. The NO-cGMP signaling is activated by the AT1R subtype, whereas the Ang type 2 receptor has no effect.
Another important signal molecule, NADPH oxidase, was studied because activation of NADPH oxidase by Ang II and subsequent O2•− generation can reduce the NO bioavailability.15,16 We found that incubation of proximal tubules with Ang II stimulated NADPH oxidase in all of the experimental groups, but the effect of Ang II on O2•− generation was much higher in BSO-treated rats. Tempol supplementation of BSO-treated rats normalized the Ang II-mediated NADPH oxidase activation, suggesting that excessive Ang II-mediated O2•− production could be because of AT1R upregulation and may, therefore, be responsible for NO inactivation. Also, in BSO-treated rats, Ang II-mediated, NOS-dependent O2•− production was mediated by AT1R and was abolished by Tempol, suggesting the role of oxidative stress in NOS uncoupling. In the present study we cannot distinguish whether the NOS uncoupling was because of BSO-induced oxidative stress or AT1R upregulation and subsequent O2•− production. However, irrespective of the cause for NOS uncoupling, these data show that NO inactivation may lead to sustained and exaggerated AT1R signaling, which, in turn, may contribute to hypertension.
The intracellular signaling events that link AT1R stimulation to an increase in NADPH oxidase activity and O2•− production are unclear at present. Indirect evidence suggests that PyK2 might be upstream of oxidase activation.15,28,29 The time course of PyK2 phosphorylation by Ang II parallels closely that of NADPH oxidase activation, and PyK2 and Rac-1 form a complex in response to Ang II in smooth muscle cells.15,28,29 We found that Ang II-mediated PyK2 phosphorylation paralleled O2•− production in BSO-treated rats, because both were significantly higher than in other groups, and Tempol normalized the Ang II-mediated PyK2 phosphorylation and NADPH oxidase activation in BSO-treated rats. These data show that upregulation of AT1R could lead to overactivation of PyK2, which, in turn, caused excessive O2•− production via NADPH oxidase activation in BSO-treated rats.
In conclusion, we have shown that oxidative stress-mediated renal AT1R upregulation causes loss of biphasic effect of Ang II on NKA regulation and hypertension. The upregulated AT1R not only caused overstimulation of NKA at lower Ang II concentration but failed to show inhibition at higher concentration. The loss of inhibition was because of failure of Ang II to stimulate NO-cGMP signaling. Most importantly, Ang II via AT1R caused exaggerated PyK2 activation, which, in turn, led to robust O2•− generation that may have contributed to NO inactivation and NOS uncoupling and subsequently disrupted Ang II-AT1-NO-cGMP pathways. Antioxidant Tempol reduced oxidative stress and normalized AT1R signaling and reduced BP.
The biphasic effect of Ang II on NKA is quite unique and potentially relevant, because it relates to the control of proximal tubular sodium reabsorption under normal and pathophysiological conditions. In the present study we used the pharmacological inhibitor of the glutathione pathway to produce oxidative stress in Sprague-Dawley rats and studied the mechanism by which the effect of Ang II on NKA was altered. These studies provide an insight as to how oxidative stress may lead to AT1R upregulation, disturb sodium homeostasis, and contribute to the development of hypertension.
Sources of Funding
This study was supported by Scientist Development grant 0835428N from American Heart Association (to A.A.B.) and National Institutes of Health grant AG-25056 from the National Institute on Aging (M.F.L.).
- Received June 9, 2008.
- Revision received June 28, 2008.
- Accepted October 3, 2008.
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