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. Author manuscript; available in PMC: 2011 Jun 1.
Published in final edited form as: Hypertension. 2010 Apr 19;55(6):1425–1430. doi: 10.1161/HYPERTENSIONAHA.110.151332

ROLE OF RENAL PERFUSION PRESSURE VERSUS ANGIOTENSIN II ON RENAL OXIDATIVE STRESS IN ANGIOTENSIN II-INDUCED HYPERTENSIVE RATS

Aaron J Polichnowski 1, Chunhua Jin 1, Chun Yang 1, Allen W Cowley Jr 1
PMCID: PMC2884003  NIHMSID: NIHMS198694  PMID: 20404214

Abstract

Renal oxidative stress is thought to contribute to both the etiology and the associated renal injury in AngII-dependent hypertension. The contribution of AngII versus elevated renal perfusion pressure (RPP) on albuminuria and renal oxidative stress in this model of hypertension was explored in the present study by chronically servocontrolling RPP to the left kidney and comparing responses to the right uncontrolled kidney and to the left kidney of sham rats. Hypertension was produced in Sprague-Dawley rats fed a 4% NaCl diet by chronic i.v. infusion of AngII (25 ng/kg/min). The RPP to the left kidney was servocontrolled to mean daily pressures averaging ~120 mmHg while the uncontrolled kidneys averaged ~170 mmHg over 14 days of AngII-infusion. AngII infusion resulted in a 2.4-fold increase in albuminuria, which was RPP-dependent. Kidneys exposed to both elevated RPP and AngII (uncontrolled kidneys) displayed a 3.5-fold increase in malondialdehyde excretion and a 37% and 27% increase in renal cortical and outer medullary superoxide production, respectively. Elevated RPP significantly contributed to global renal oxidative stress (70% increase in malondialdehyde excretion) and outer medullary superoxide production. Elevated circulating levels of AngII, per se, were responsible for a 1.5-fold and 2-fold increase in renal cortical and outer medullary NADPH oxidase activity, respectively. In summary, this study demonstrates that elevated RPP is directly responsible for the excess albuminuria in AngII-infused rats while both elevated RPP and AngII directly contribute to the observed renal oxidative stress.

Keywords: angiotensin, blood pressure, kidney, oxidative stress, renal injury

Introduction

Excess levels of superoxide (O2·−) are found within the kidney of angiotensin II (AngII)-dependent hypertensive rats 1, 2 and have been associated with both the etiology and injury in this form of hypertension 2–6. Both elevated AngII 2, 4, 5 and RPP 7 have been reported to independently increase renal O2·− production; however, the precise contribution of each on O2·− production within different regions of the kidney of AngII-induced hypertensive rats remains incomplete. We investigated the relative contributions of RPP and AngII on albuminuria, the in vivo production of renal reactive oxygen species (ROS), as well as the activities of NADPH oxidase and superoxide dismutase (SOD) in renal cortical and outer medullary tissue homogenates. We focused on these two enzyme systems as they have previously been reported to contribute importantly to the excess O2·− production in kidneys of AngII-induced hypertensive rats 2. As we have previously described 6, 8, a custom-built computerized servocontrol system of our own design was used to maintain RPP to the left kidney at baseline levels while the contra lateral right kidney was exposed to elevated RPP over 14 days of AngII administration. This system enabled the precise determination of the role of AngII versus elevated RPP in contributing to renal oxidative stress and pathways of O2·− production and scavenging within the renal cortex and outer medulla during hypertension.

Materials and Methods

Experimental Animals

All studies were performed on 12 week old male Sprague-Dawley rats (Harlan) that were provided water ad libitum and given a 0.4% NaCl AIN-76 rodent diet (Dyets, Bethlehem, PA). All protocols were approved by the Medical College of Wisconsin Institutional Animal Care and Use Committee.

Surgical Preparation and Chronic Servocontrol of RPP

As described previously 6, 8, all rats were implanted with indwelling catheters in the right carotid and left femoral artery and vein and an inflatable silastic vascular occluder (1.5 mm lumen diameter, 2.5 mm outer diameter; Kent Scientific Corp., Torrington, CT) was positioned around the aorta between the left and right renal arteries to allow for chronic servocontrol of left RPP. Sham rats underwent identical surgical and implantation procedures; however, the vascular occluder cuff was never inflated. Arterial pressure above (carotid artery) and below (femoral artery) the vascular occluder cuff was monitored 24 hrs/day throughout the study. Saline or drug was continuously administered i.v. at a rate of 6.9 μL/min throughout the study.

One group of rats was anesthetized with ketamine (30 mg/kg i.m.) and inactin (40 mg/kg i.p.) for bilateral ureteral urine collections following the 2-week administration of AngII or saline. Rats were placed on a 37° C warming board and AngII infusion and servocontrol of left RPP were continued uninterrupted throughout the acute protocol. A tracheal tube was inserted to facilitate spontaneous respiration and a catheter was implanted in the right femoral vein for the infusion (1 ml/hr/100g body weight) of 2% bovine serum albumin to replace fluid loss during surgery. Through a midsagital incision, the right and left ureters were catheterized with PE-10 tubing for the collection of urine. After a 1-hour equilibration period, urine was collected over two 30-minute intervals and immediately snap frozen and stored at −80° C.

Experimental Design

Following four days of recovery from surgery, the diet of all rats was switched to a 4.0% NaCl AIN-76 rodent diet (Dyets, Bethlehem, PA) for the remainder of the study. Rats were recovered for 10 days following surgery during which 3 days of baseline blood pressure were recorded. The intravenous infusion solution was then switched to either AngII (25 ng/kg/min) for servocontrol rats or saline for sham operated rats. The chronic servocontrol of RPP began immediately following the infusion of AngII and left RPP (femoral arterial pressure) was maintained within ± 10 mmHg of baseline pressures while the right kidney was exposed to elevated RPP throughout the 2 weeks of AngII infusion. Two separate groups of rats were studied. Rats of group 1 were acutely anesthetized for bilateral ureteral urine collections following either 14 days of AngII (n=6) or saline (n=7) infusion, as described above. Albumin excretion was measured as a physiological index of renal damage and malondialdehyde excretion was measured as an in vivo index of oxidative stress, as described below. Following 14 days of AngII (n=9) or saline (n=10) infusion, rats of group 2 were euthanized by excess sodium pentobarbital (100 mg/kg) and the cortex and outer medulla were quickly separated and immediately snap frozen in liquid nitrogen. Tissues from 3 AngII-infused rats and 4 sham rats from group 1 were included in the tissue homogenate analysis in group 2. The frozen tissue was then homogenized, centrifuged at 1000g for 5 minutes, and the protein concentration of the supernatant was determined using a Coomassie blue protein assay (Pierce; Rockford, IL) with bovine serum albumin used as a standard9.

O2·− Production by 2-Hydroxyethidium Measurements

Renal cortical and outer medullary tissue homogenates (20 μg protein) were incubated with dihydroethidium (10 μM), salmon testes DNA (0.5 mg/mL), and phosphate buffered saline (300 mM) in a 96-well microtiter plate to determine O2·− production. NADPH oxidase-dependent O2·− production was assessed by adding 100 μM diphenylene iodonium (DPI) to tissue homogenates (20 μg protein) in separate wells to determine the decrease in O2·− production as compared to wells not incubated with DPI. This dose of DPI maximally inhibits NADPH oxidase and we have previously used this approach to identify differences in NADPH oxidase activity in Dahl S versus SS.BN13 rats 9. Following a 35-minute incubation, the increase in 2-Hydroxyethidium fluorescence was measured at an excitation of 485 nm and an emission of 570 nm and used as an index of O2·− production, as described previously 9.

Total SOD Activity

Total SOD activity was determined in renal cortical and outer medullary tissue homogenates by the disappearance of superoxide detected by a tetrazolium salt, as described previously 9.

Measurement of Creatinine, Albumin and Malondialdehyde in Urine

Urine samples were centrifuged at 5,000g for 10 minutes to remove debris following which urine volumes were measured gravimetrically. Urine samples were stored at −80° C until determination of creatinine, albumin and malondialdehyde. Urinary creatinine was quantified using an assay based on the Jaffe’ Reaction by autoanlayzer (ACE; Alfa Wasserman, Fairfield, NJ). Urinary albumin was quantified with Albumin Blue 580 dye (Molecular probes) using a fluorescent plate reader (FL600, Bio-Tek). Malondialdehyde, a product of lipid peroxidation and an index of oxidative stress, was measured in urine samples using a Thiobarbituric Acid Reactive Substances kit obtained from Caymen.

Statistical Analysis

Data are presented as mean ± SE. A two-way repeated measures ANOVA followed by a Tukey post hoc test was used to determine daily differences in RPP across sham, servocontrolled, and uncontrolled kidneys. A paired t-test was used to assess differences between servocontrolled and uncontrolled kidneys while an unpaired t-test was used to assess differences between uncontrolled kidneys and kidneys from sham rats. Pearson correlation and linear regression analysis were performed for sham, servocontrolled, and uncontrolled kidneys to assess the relationship between the average RPP over the 14-day infusion protocol and both albuminuria and malondialdehyde excretion. A p<0.05 was considered significant.

Results

RPP of Sham, Servocontrolled, and Uncontrolled Kidneys

Figure 1 summarizes the average RPP to servocontrolled and uncontrolled kidneys of AngII-infused rats (n=12) as well as kidneys of saline-infused rats (n=13). The right uncontrolled kidneys of these rats were exposed to an average RPP of nearly 170 mmHg over the 14 days of AngII infusion while RPP to servocontrolled kidneys was maintained within ± 10 mmHg of the baseline RPP. There were no significant differences in RPP between the sham rats and the servocontrolled kidneys of the AngII infused rats across all time points.

Figure 1.

Figure 1

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Daily 24 hour averages of MAP in the left femoral artery, used as an index of the left servocontrolled RPP (□, n=12), and in the right carotid artery, used as an index of right uncontrolled RPP (■, n=12) in chronically servocontrolled rats infused i.v. with AngII (25 ng/kg/min) for 2 weeks. The 24-hour average of MAP in the left femoral artery of sham rats (▲, n=13) was used as an index of left RPP in these rats. Values are mean ± SE. † p < 0.05 vs. servocontrolled and sham groups over days 1–14.

Urinary Albumin and Malondialdehyde Excretion

As determined on day 14 of the study in the anesthetized rats (Figure 2), elevated RPP resulted in a greater (p<0.05) urinary albumin:creatinine ratio (ACR) in uncontrolled kidneys (3.54 ± 0.7 mg/mg) as compared to both servocontrolled kidneys (1.39 ± 0.4 mg/mg) and kidneys from sham rats (1.45 ± 0.2 mg/mg). A significant (p<0.05) correlation existed between the ACR and the average RPP over the 14 days of AngII infusion (r=0.68) among all kidneys. No significant differences in ACR were observed between servocontrolled kidneys and kidneys from sham rats. Using ACR as an index of renal injury, these data indicate that the renal injury in AngII-infused hypertensive rats was primarily due to elevated RPP.

Figure 2.

Figure 2

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Summary of albumin:creatinine ratio in servocontrolled (n=6) and uncontrolled (n=6) kidneys from AngII-infused rats and kidneys from sham rats (n=7). Elevated RPP was directly responsible for the increased albumin:creatinine ratio observed in AngII-infused rats. Values are mean ± SE.

There was a 3.5 fold increase in malondialdehyde excretion, an in vivo index of oxidative stress (Figure 3), in uncontrolled kidneys versus kidneys from sham rats. Elevated RPP directly led to a 1.7 fold (p<0.05) increase in renal oxidative stress, as demonstrated by the higher malondialdehyde excretion in uncontrolled (0.47 ± 0.07 nmol/min) compared to servocontrolled kidneys (0.28 ± 0.05 nmol/min). Furthermore, there was a significant (p<0.05) correlation between malondialdehyde excretion and the average RPP across 14-days of infusion (r=0.8) among all kidneys. The source of the greater levels of malondialdehyde excreted from the uncontrolled kidneys could have been either from the renal cortex or medulla, but not from non-renal sources since such changes would have been reflected by excretion from both kidneys. The MAP over the two 30-minute urine collection periods averaged 149 ± 13 mmHg in uncontrolled kidneys and 124 ± 11 mmHg in servocontrolled kidneys. Since these pressures were well within the autoregulatory range of renal blood flow 10 and glomerular filtration rate 7, differences in malondialdehyde excretion between servocontrolled and uncontrolled kidneys cannot be explained in this way. These data provide evidence that elevated RPP significantly contributes to renal oxidative stress in AngII-induced hypertensive rats.

Figure 3.

Figure 3

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Summary of malondialdehyde excretion, an index of in vivo oxidative stress, in servocontrolled (n=6) and uncontrolled (n=6) kidneys from AngII-infused rats and kidneys from sham rats (n=7). Elevated RPP, per se, led to a 70% increase in renal oxidative stress. Values are mean ± SE.

Malondialdehyde excretion was 2-fold (p<0.05) higher in servocontrolled kidneys compared to kidneys from sham rats (0.13 ± 0.01 nmol/min). This difference in malondialdehyde excretion between servocontrolled kidneys and kidneys from sham rats could have resulted from sources other than the kidney and thus, does not provide direct evidence of AngII-induced stimulation of renal oxidative stress. The pressure independent effects of AngII on renal oxidative stress are demonstrated by the tissue assay of O2·− production described below.

In Vitro Renal O2·− Production, NADPH Oxidase and SOD Activity

Figure 4 summarizes O2·− production, reported in raw fluorescent units (RFU), in renal cortical and outer medullary tissue homogenates in servocontrolled and uncontrolled kidneys from AngII-infused rats and kidneys from saline-infused sham rats. In the renal cortex, there was a 32% and 37% increase in O2·− production in servocontrolled and uncontrolled kidneys, respectively, from AngII-infused rats as compared to kidneys from saline-infused sham rats (p<0.05). These data indicate that AngII, independent of RPP, was the primary contributor to O2·− production in the renal cortex. In the outer medulla, there was a 17% (p<0.05) and 27% (p<0.05) increase in O2·− production in servocontrolled and uncontrolled kidneys, respectively, from AngII-infused rats as compared to kidneys from saline-infused sham rats. In contrast to the renal cortex, elevated RPP significantly increased O2·− production in the outer medulla as indicated by the significantly higher RFU in uncontrolled versus servocontrolled kidneys (p<0.05). Furthermore, O2·− production was higher (p<0.05) in the outer medulla versus cortex among all kidneys.

Figure 4.

Figure 4

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Average O2·− production, expressed as 2-hydroxyethidium raw fluorescent units (RFU), in renal cortical and outer medullary tissue homogenates from servocontrolled (n=9) and uncontrolled kidneys (n=9) from AngII-infused rats and kidneys from saline-infused sham rats (n=10). Elevated AngII independently increased O2·− production in both the cortex and outer medulla, whereas elevated pressure led to a significant increase in O2·− production only within the outer medulla. In all kidneys, outer medullary O2·− production was significantly greater as compared to the renal cortex. Values are mean ± SE. † p < 0.05 vs. cortex for all kidneys.

As summarized in Figure 5, chronic AngII infusion resulted in an increase in NADPH oxidase-dependent O2·− production. This was a consequence of elevated levels of circulating AngII, per se, as shown by the 1.5-fold and 2-fold greater (p<0.05) inhibition of O2·− production by DPI in the renal cortex and outer medulla, respectively, in both servocontrolled and uncontrolled kidneys from AngII-infused rats as compared to kidneys from sham rats.

Figure 5.

Figure 5

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Index of NADPH-oxidase dependent O2·− production, expressed as the decrease in 2-hydroxyethidium raw fluorescent units (RFU) in the presence of 100 μM DPI, an inhibitor of NADPH oxidase, in renal cortical and outer medullary tissue homogenates from servocontrolled (n=9) and uncontrolled (n=9) kidneys of AngII-infused rats and kidneys from sham rats (n=10). Elevated AngII, per se, resulted in a 2-fold greater inhibition of O2·− production in the outer medulla and a 1.5-fold greater inhibition of O2·− production in the cortex. Elevated RPP did not significantly alter NADPH oxidase activity in tissue homogenates from either the cortex or outer medulla. Values are mean ± SE.

As shown in Figure 6, renal cortical SOD activity was not significantly altered by elevated AngII or RPP. However, outer medullary SOD activity in uncontrolled kidneys (2.0 ± 0.2 U/mL/ug protein) exposed to both elevated AngII and RPP was 28% (p<0.05) lower as compared to kidneys from sham rats (2.7 ± 0.2 U/mL/ug protein). AngII directly accounted for 12% of this reduction in SOD activity while elevated RPP was responsible for the remaining 16% reduction, although neither of these values individually reached statistical significance. These data suggest that the significant decrease in outer medullary SOD activity in AngII-infused hypertensive rats may be explained by the additive effects of elevated AngII and RPP.

Figure 6.

Figure 6

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SOD activity in renal cortical and outer medullary tissue homogenates from servocontrolled (n=9) and uncontrolled (n=9) kidneys of AngII-infused rats and kidneys from sham rats (n=10). No significant differences in SOD activity were present in the renal cortex among all kidneys, whereas AngII and RPP had additive effects on suppressing outer medullary SOD activity. Values are mean ± SE.

Discussion

The major findings of the present study were that following 2 weeks of AngII-induced hypertension: 1) elevated RPP, per se, is the major contributor to albuminuria, 2) both elevated RPP and AngII independently contribute to renal oxidative stress and 3) AngII, independent of elevated RPP, increases NADPH oxidase activity in the renal cortex and outer medulla.

RPP-induced Albuminuria

AngII-induced hypertension results in significant renal injury 6, 11, 12, which can lead to the appearance of excess levels of albumin excretion 13. This is the first study that directly implicates chronically elevated RPP as the primary cause of the increased albuminuria in AngII-induced hypertension in rodents. These observations are consistent with our previous histological analyses showing that elevated RPP is responsible for the majority of the juxtamedullary glomerulosclerosis and the interstitial fibrosis in the outer medulla found in AngII-induced hypertension 6, 12.

Hypertension-induced albuminuria has been reported to result from podocyte injury with the subsequent loss of the glomerular filtration barrier 14–16. Mechanical forces related to RPP-induced increases in glomerular capillary pressure, such as shear stress and stretch, have been reported to alter the structure and function of podocytes, which can ultimately lead to an increase in the permeability of the glomerular filtration barrier to albumin 16–18. Our study demonstrates that it is mainly the lowering of arterial pressure that is the most important factor in normalizing albuminuria in AngII-induced hypertensive rodents. As reviewed previously 19, this is in agreement with several clinical trials and emphasizes the importance of blood pressure control in the prevention of renal injury.

RPP-induced Superoxide Production

The 1.7 fold greater urinary excretion of malondialdehyde in uncontrolled versus servocontrolled kidneys provides evidence that chronically elevated RPP, independent of AngII, results in renal oxidative stress in the AngII-induced model of hypertension. It is relevant that the RPP-dependent stimulation of renal oxidative stress was much more apparent in the intact kidney based on malondialdehyde excretion compared to O2·− production in tissue homogenates, where only a small RPP-induced effect was observed in the outer medulla. This suggests that mechanisms within the context of the intact kidney are necessary to enable increases of RPP to fully stimulate oxidative stress. It is likely that the critical signals required for elevations of RPP to stimulate oxidative stress are lost when the kidney is removed, tissue homogenized and incubated for the various assay studies. Mechanical forces associated with increased levels of RPP, such as stretch and/or shear stress, can increase O2·− production in blood vessels and mesangial cells 20–24. In isolated perfused mTAL, we and others have demonstrated that increases in tubular flow rate 25, 26, stretching 27, and delivery of luminal NaCl 25 increase O2·− production. Furthermore, we have found that acute increases of RPP within the kidney autoregulatory range stimulate the production of H2O2 within the renal outer medulla 7. These studies support the stimulation of renal oxidative stress by mechanical forces, which may have resulted in the greater amount of RPP-induced oxidative stress observed in the intact kidney versus tissue homogenates.

The specific sources of RPP-induced oxidative stress remain to be determined. Increased NADPH oxidase activity and reduced SOD activity are two commonly reported sources of the excess O2·− levels observed in kidneys of AngII-infused rats. Based on the activity of these enzymes in tissue homogenates, the present study suggests that only outer medullary SOD activity is influenced by chronically elevated RPP. It is apparent that NADPH oxidase activity is significantly elevated by AngII, independent of RPP, in both the renal cortex and outer medulla. While these results are direct evidence of a RPP-independent effect of AngII to increase NADPH oxidase activity, they do not discount a role of RPP-induced stimulation of NADPH oxidase. For example, several of the mechanical forces that have been reported to stimulate renal O2·− production, as described in the previous paragraph, operate through NADPH oxidase 22, 23, 26. It is possible that the lack of RPP-induced stimulation of NADPH oxidase activity in tissue homogenates was the result of NADPH-oxidase-induced O2·− production being assessed in vitro and thus removed from the various in vivo mechanical stimuli, as described above. In summary, our study demonstrates that elevated RPP significantly contributes to renal oxidative stress in AngII-induced hypertensive rats and suggests that in vivo detection of renal oxidative stress may be necessary to detect the full extent of RPP-induced oxidative stress.

AngII-induced Superoxide Production

Independent of changes of RPP, O2·− production and NADPH oxidase activity were significantly enhanced by AngII, per se, in both renal cortical and outer medullary tissues. As demonstrated in Figure 5, NADPH oxidase activity was increased to a similar extent in both the cortex and outer medulla by the direct effects of AngII. This unequivocal demonstration of the direct actions of AngII on NADPH oxidase activity are consistent with observations by others 2, 4, 28 and appear to be mediated through AT-1 receptor pathways. The use of the servocontrol system uniquely enabled the in vivo separation of the direct effects of AngII upon these enzymes from the physical forces upon the kidney that inevitably occur with hypertension. Even chronic subpressor infusion of Ang II in rats appear capable of simulating oxidative stress as shown by increased plasma concentrations of 8-isoprostanes 29 and increased expression of genes related to oxidative stress and extracellular matrix formation in the renal outer medulla 30. Although much work remains regarding the acute and chronic cellular mechanisms by which AngII stimulates NADPH oxidase in different renal structures, this is the first study to demonstrate that renal NADPH oxidase activity can be directly regulated by AngII, per se, in AngII-induced hypertensive rats. As recently reviewed 31, excess ROS production within the kidney can stimulate sodium reabsorption and vasoconstriction, both of which can result in a rightward shift in the long-term pressure-natriuresis curve and lead to hypertension. Consistent with previous studies 2, 28, our study supports a direct role of AngII-induced stimulation of NADPH oxidase to contribute to the pro-hypertensive actions of AngII.

Perspectives

The consequence of reduced renal function in the initiation of many experimental and human forms of hypertension has long been established 32, 33. On the other hand, the extent to which the secondary effects of elevated arterial pressure can lead to further renal dysfunction and injury has remained a difficult question to answer. It is recognized that renal injury is minimal in some individuals with hypertension while end-stage renal disease develops at an early age in others 34, 35. The question of the how much RPP contributes directly to the renal injury and the participating mechanisms is important as it relates to how vigorously one should pursue the lowering of arterial pressure of hypertensive individuals and by what means. It is unlikely that the chronic impact of arterial pressure upon the kidneys could ever be directly addressed in human subjects in a manner that enables the independent control of the critical variable, renal arterial perfusion pressure. However, an awareness of these issues is reflected by several clinical trials to ascertain the effectiveness of various antihypertensive drug combinations in reducing renal and cardiac injury 36, 37. Several studies from our laboratory have now begun to unravel some aspects of this chicken and egg conundrum using experimental animal models that mimic various forms of the human condition 6, 8, 12. Much remains to be done, especially with regard to an understanding of how genetic background can predispose an individual to renal injury in the face of elevated arterial pressure and the pathways that could be therapeutically targeted to minimize such effects.

Acknowledgments

The authors thank David Eick, Mike Kloehn, and Greg McQuestion for design and maintenance of the servocontrol system and Lisa Henderson, Jenifer Goepfert, and Camille Torres in the Biochemical Core Laboratory for the measurement of albumin and malondialdehyde.

Sources of Funding

This work was supported by National Heart, Lung, and Blood Institute grants HL-081091 and HL-29587 and predoctoral fellowship from American Heart Association AHA-0615590Z.

Footnotes

Disclosures

None

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