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(Hypertension. 2001;37:541.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Increased Oxidative Stress in Experimental Renovascular Hypertension

Lilach O. Lerman; Karl A. Nath; Martin Rodriguez-Porcel; James D. Krier; Robert S. Schwartz; Claudio Napoli; J. Carlos Romero

From the Department of Internal Medicine, Divisions of Hypertension (L.O.L., J.D.K.), Nephrology (K.A.N.) and Cardiovascular Diseases (R.S.S.), and the Department of Physiology and Biophysics (J.C.R.), Mayo Clinic, Rochester, Minn; the Department of Medicine, University of Naples, Italy (C.N.); and the Department of Medicine-0682, University of California, San Diego, Calif (C.N.).

Correspondence to Lilach O. Lerman, MD, PhD, Division of Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail lerman.lilach{at}mayo.edu

	Abstract

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The pathophysiological mechanisms responsible for maintenance of chronic renovascular hypertension remain undefined. Excess angiotensin II generation may lead to release of reactive oxygen species and increased vasoconstrictor activity. To examine the potential involvement of oxidation-sensitive mechanisms in the pathophysiology of renovascular hypertension, blood samples were collected and renal blood flow measured with electron-beam computed tomography in pigs 5 and 10 weeks after induction of unilateral renal artery stenosis (n=7) or sham operation (n=7). Five weeks after procedure, plasma renin activity and mean arterial pressure were elevated in hypertensive pigs. Levels of prostaglandin F2 (PGF₂)–isoprostanes, vasoconstrictors and markers of oxidative stress, also were significantly increased (157±21 versus 99±16 pg/mL; P<0.05) and correlated with both plasma renin activity (r=0.83) and arterial pressure (r=0.82). By 10 weeks, plasma renin activity returned to baseline but arterial pressure remained elevated (144±10 versus 115±5 mm Hg; P<0.05). Isoprostane levels remained high and still correlated directly with the increase in arterial pressure (r=0.7) but not with plasma renin activity. Stenotic kidney blood flow was decreased at both studies. In shock-frozen cortical tissue, ex vivo endogenous intracellular radical scavengers were significantly decreased in both kidneys. The present study demonstrates, for the first time, that in early renovascular hypertension, an increase in plasma renin activity and arterial pressure is associated with increased systemic oxidative stress. When plasma renin activity later declines, PGF₂-isoprostanes remain elevated, possibly due to local activation or slow responses to angiotensin II, and may participate in sustenance of arterial pressure. Moreover, oxidation-sensitive mechanisms may influence ischemic and hypertensive parenchymal renal injury.

Key Words: hypertension, renal • angiotensin II • stress, oxidative • isoprostanes • renin

	Introduction

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Renal artery stenosis is a major cause of renovascular hypertension (RVH) and may lead to ischemic nephropathy and end-stage renal disease. The role of the renal vasculature in eliciting RVH had been established as early as 1934, when Goldblatt et al¹ demonstrated that partial obstruction of the renal artery increased mean arterial pressure (MAP). Nevertheless, to date, the mechanism responsible for maintenance of chronic RVH remains undefined.²

Involvement of the renin-angiotensin system in pathogenesis of this disorder has been well established but is puzzling given the near-normal circulating levels of angiotensin II (Ang II) often observed in chronic RVH.³ Researchers have speculated that RVH may be maintained by enhanced vascular responsiveness to the slow pressor effect of Ang II.⁴ This phenomenon is characterized by a gradual increase of MAP that can be induced by chronic systemic infusion of Ang II (over a period of 3 to 5 days) in subpressor doses, which are too low either to significantly increase its circulating levels or to evoke an immediate increase in MAP.⁵ We recently showed^{6 7} that development of slow responses to Ang II (during chronic systemic infusion of low-dose Ang II) was accompanied by an Ang II–induced increase of one of the systemic oxidative stress markers, prostaglandin F2 (PGF₂)–isoprostanes, the potential effects of which include a decrease in renal blood flow (RBF), sodium retention, and vasoconstriction.^{8 9} Such effects not only could play a role in development of slow responses to Ang II, but also could mediate and be more directly linked with sustenance of RVH than circulating Ang II levels. Because of ischemia and high intrarenal Ang II levels,¹⁰ the stenotic kidney conceivably could be a source of such mediators.

Nevertheless, the involvement of oxidation-sensitive mechanisms in the pathophysiology of RVH rather than exogenous Ang II infusion has not been fully explored.^{2 7} Thus, the present study was designed to examine the hypothesis that unilateral renal artery stenosis increased activation of oxidation-sensitive mechanisms in systemic circulation and stenotic kidney.

	Methods

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Fourteen domestic female pigs were studied at baseline and 5 and 10 to 12 weeks after induction of renal artery stenosis (group 1; n=7), or after sham operation (group 2; n=7). In each study, systemic and renal vein blood samples were collected for measurement of PGF₂-isoprostanes and plasma renin activity (PRA), degree of stenosis was determined by use of quantitative renal angiography, and RBF was measured with electron-beam computed tomography (EBCT). MAP was monitored continually with an implanted telemetry system. After completion of studies, kidneys were removed for assessment of renal parenchymal oxidation (endogenous tissue oxygen radical scavengers). The present study was performed according to institutional and National Institutes of Health (Bethesda, Md) guidelines for the care and use of laboratory animals.

Animal Preparation
On the day of the baseline study, each animal was anesthetized intramuscularly with 0.5 g of ketamine, intubated, and mechanically ventilated. Anesthesia was maintained with a mixture of 30 mg/kg of ketamine and 3 mg/kg of xylazine in normal saline (1 to 2 mL/min). Under sterile conditions and fluoroscopic guidance, an 8F catheter was advanced through the left carotid artery and positioned at the level of the renal arteries, and saline infusion (1.5 mL/min) was initiated. MAP was monitored online through a side arm of this catheter. A guide catheter was also advanced through the left jugular vein to the renal veins and inferior vena cava for collection of blood samples and was then positioned in the superior vena cava for contrast injections during EBCT studies. A nonionic, low-osmolar contrast medium (iopamidol, Isovue-370, Squibb Diagnostics) was used throughout the study.

Animals then were transferred to the EBCT (Imatron C-150, Imatron Inc) scanning gantry, and a renal flow study was performed as previously described.¹¹ Briefly, 40 sequential EBCT scans (50 ms per image) were obtained at varying time intervals (for a total scanning time of 3 minutes) over 2 preselected, 8-mm-thick tomographic levels at the mid-hilar plane of both kidneys. Scanning was initiated 4 seconds after a bolus injection (0.5 mL/kg over 1 s) of iopamidol into the central venous catheter. After a 15-minute recovery period, a renal volume study was performed, in which both kidneys were scanned from pole to pole during iopamidol infusion (5 mL/s), as previously described.¹²

Animals were returned to the fluoroscopy suite, and selective renal angiography was performed. At the baseline study, unilateral renal artery stenosis was induced in group 1 by implantation of a local-irritant stent device in the left renal artery, as previously described.¹² The device produces a gradual and progressive stenosis of the renal artery, followed by an increase in MAP within an average of 10 days.¹² Repeated fluoroscopy excluded acute obstruction, and pigs received a standard postoperative analgesic and antibiotic regimen.

During repeated studies, femoral vessels were used for vascular access and the right carotid artery and jugular vein remained intact. EBCT flow and volume studies, sample collection, and renal angiography were repeated as described above. Selective-contrast injections were used to visualize the renal arterial lumen. Degree of stenosis was determined offline from the images by use of a standard quantitative coronary angiography system through assessment of the decrease in luminal diameter compared with a stenosis-free segment.¹² On completion of each EBCT ("acute") study, all catheters were removed, and the access vessels ligated.

Blood Pressure Measurement
Continuous ("chronic") blood pressure recording was obtained by use of a PhysioTel telemetry system (Data Sciences) implanted at baseline in the left carotid artery after catheter withdrawal as previously described.¹² MAP was recorded at 5-minute intervals and averaged for each 24-hour period. Levels reported (Table 1) were those obtained for 2 days before each study.

View this table: [in this window] [in a new window]   Table 1. Systemic Characteristics of Pigs Before and After Induction of Unilateral Renal Artery Stenosis vs Normal, Sham-Operated Pigs

After completion of the series of experiments, pigs were allowed to recover and were euthanatized 2 to 4 days later (to ensure complete renal recovery and contrast clearance). Kidneys were dissected, immediately sliced into sections, shock-frozen in liquid nitrogen, and maintained at -80°C.

EBCT Image Analysis
EBCT images were reconstructed by use of a standard tomographic algorithm and displayed on a Sun System computer workstation with the Analyze software package (Biomedical Imaging Resource, Mayo Foundation). Regions of interest were selected from cross-sectional images from the aorta and bilateral renal cortex and medulla.¹¹ Average density of each sampled region was plotted as a function of time,¹¹ and time-density curves were fitted with modified gamma-variate functions.¹³ The area and first moment of each vascular curve were obtained, and perfusion (in milliliters per minute per cubic centimeter of tissue) was calculated as previously detailed^{11 12 13} : Area Under Tissue CurvexArea Under Aortic Curve^-1xFirst Moment of Tissue Curve^-1x60.

Cortical and medullary volumes (in cubic centimeters) were calculated from the images by use of a program implemented in Analyze.¹² RBF was subsequently calculated for each kidney as the sum of the products of its cortical and medullary perfusions and corresponding volumes.¹²

Biochemical Determinations
PRA was determined in both systemic and renal venous blood using a standard radioimmunoassay technique.⁶ PGF₂-isoprostanes and thiobarbituric acid–reactive substances (TBARS), plasma markers of a pro-oxidant redox status, were measured with enzyme immunoassay and spectrophotometric measurement of TBARS (at 532 nm), respectively, as previously described.^{6 14} Tissue activities of the oxygen-radical scavengers glutathione peroxidase, catalase, copper-zinc form of superoxide dismutase (CuZn-SOD), and Mn-SOD were determined in homogenized flash-frozen renal cortical tissue. Briefly, glutathione peroxidase activity was assayed spectrophotometrically from the rate of oxidation of NADPH at 22°C, catalase activity from the reduction of hydrogen peroxide (rate of decrease of absorbance at 240 nm) at 25°C, and SOD activity on the basis of the spontaneous autoxidation of pyrogallol at 25°C (with formation of end products at an absorbance peak at 420 nm) as previously described.¹⁵ To distinguish between the CuZn-SOD and Mn-SOD isoenzymes, parallel measurements were performed in the presence of 1 µmol/L KCN, a selective inhibitor of CuZn-SOD.¹⁵ All tissue activities were normalized for protein content by the Lowry method.¹⁶

Statistical Analysis
Quantitative values are expressed as mean±SEM. Statistical comparisons between different experimental periods or groups were performed using ANOVA and Student’s t test and regressions by the least-squares fit. Statistical significance was accepted at P=0.05.

	Results

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Systemic Measurements
At baseline, levels of MAP, PRA, and RBF in group 1 (Figure 1; Tables 1 and 2) were similar to levels in group 2 (99.4±6.5 mm Hg, 0.6±0.3 ng · mL^-1 · h^-1, and 396±67 mL/min; P=NS). By 5 weeks after the procedure, significant renal artery stenosis in group 1 (Table 1) was associated with a decrease in stenotic RBF (Table 2) compared with both single-kidney RBF of group 2 at their 5-week study (535±37 mL/min; P=0.008) and contralateral kidney (Table 2; P=0.01). MAP increased by 29% (Figure 1; P=0.005). PRA strongly tended to increase (Figure 1; P=0.06), lateralized to the stenotic kidney, and directly correlated with MAP (r=0.63; P=0.037). By 10 weeks of RVH, stenotic kidney RBF was still decreased, contralateral RBF was significantly higher than in group 2 (Table 2), and MAP remained elevated (Table 1). However, PRA returned to baseline levels (Figure 1; P=0.3 versus baseline) and no longer correlated with MAP (r=-0.14; P=0.77).

View larger version (26K): [in this window] [in a new window]   Figure 1. MAP (a) systemic levels of PRA (b) and total PGF2-isoprostanes (c) in pigs before (n=7) and 5 (n=6) and 10 weeks after (n=7) induction of renal artery stenosis vs in 7 normal pigs. In the early phase of RVH, both PRA and isoprostanes increased. However, in the chronic phase, PRA returned to baseline but levels of isoprostanes remained elevated. *P=0.05 vs baseline; P=0.05 vs normal.

View this table: [in this window] [in a new window]   Table 2. Single-Kidney Characteristics in Pigs Before and After Induction of Unilateral Renal Artery Stenosis (n=7) vs Normal, Sham-Operated Pigs

Baseline systemic levels of isoprostanes were similar in both groups. For the 5-week measurement, only 6 (rather than 7) samples of isoprostanes were available for analysis in group 1. At that time, PGF₂-isoprostanes (n=6) significantly increased in this group (Figure 1; P=0.04) and correlated with both the increase in MAP (Figure 2a, left; r=0.82; P=0.047) and PRA (Figure 2a, right; r=0.83; P=0.04). By 10 weeks, systemic isoprostanes (n=7) tended to increase further (Figure 1; P=0.07 compared with 5 weeks), and still strongly tended to correlate with the increased MAP (Figure 2b, left; r=0.75; P=0.07), but not PRA (Figure 2b, right; r=-0.36; P=0.4). Systemic TBARS levels were also significantly elevated at that time compared with normal (Table 1; P=0.005). Renal vein isoprostanes of both kidneys showed similar trends as their systemic levels (Table 2), which were stronger for total compared with free levels of PGF₂-isoprostanes (data not shown), and did not lateralize at any experimental period.

View larger version (19K): [in this window] [in a new window]   Figure 2. Correlation between systemic total PGF2-isoprostane levels measured in pigs 5 weeks (a; n=6) and 10 weeks (b; n=7) after induction of renal artery stenosis, with the change in MAP from baseline (left) and PRA (right). During the early phase of RVH, isoprostanes correlated well with both MAP and PRA, whereas during the chronic phase, they no longer correlated with PRA.

Group 2 showed no significant changes in MAP, PRA, or PGF₂-isoprostanes among the experimental periods, although their RBF increased significantly at 5 and 10 weeks compared with basal levels, probably because of growth.

Renal Parenchymal Measurements
Both the stenotic and contralateral kidneys in group 1 showed a significant and similar decrease postmortem in renal cortical levels of the oxygen-radical scavengers glutathione peroxidase, catalase, CuZn-SOD, and Mn-SOD versus group 2 (Table 2; P<0.01 for all the measurements).

	Discussion

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The present study demonstrates that experimental RVH due to unilateral renal artery stenosis is accompanied by a progressive increase in systemic plasma levels of PGF₂-isoprostanes that continues to parallel the increase in MAP even after PRA returns to baseline levels. This was associated with decreased endogenous radical-scavenger levels in both stenotic and contralateral kidneys. The present study indicates a role for increased systemic oxidative stress in the pathogenesis of RVH and for enhanced renal oxidation-sensitive mechanisms in the pathogenesis of ischemic and hypertensive renal injury.

We recently demonstrated that experimental porcine renal artery stenosis could be achieved by percutaneous deployment of an intra-arterial balloon-expandable coil that leads to progressive luminal narrowing, simulating the development of human renovascular lesions.¹² Renal tissue damage in this model can be observed only in the most severe stenoses, probably because of the relatively short duration of intervention and the absence of comorbid conditions.¹² We also previously showed that plasma Ang II levels in this model correlated well with PRA across a wide range of values and at the chronic phase of RVH were similar to normal.¹⁷ In the present study, by 1 month after induction of RVH, this model exhibited an increase in PRA that was typical of an early phase of RVH¹⁸ and lateralized to the stenotic renal vein. The fact that the increase in systemic PRA was not statistically significant (Table 1) but showed a strong trend probably reflects the variability in time course and severity of response among animals. PRA in the contralateral renal vein was also elevated, possibly because of high circulating renin levels, because the unclipped kidneys in Goldblatt hypertension showed suppressed intrarenal renin mRNA¹⁰ but Ang II–dependent renal function.¹⁹ This was paralleled by an increase in both systemic and bilateral renal-vein levels of PGF₂-isoprostanes. After 10 weeks of observation, the degree of stenosis showed little progress and MAP remained elevated. However, PRA returned to the normal levels typical for a chronic phase of RVH.¹⁸ Nonetheless, the increase in isoprostanes was maintained and still paralleled the sustained increase in MAP. RBF in the stenotic kidney was significantly decreased in both studies, underscoring the hemodynamic significance of the renal arterial stenoses achieved. By the 10-week study, RBF of the contralateral kidney was also significantly higher than normal single-kidney RBF in group 2.

One of the major factors underlying the development of RVH is activation of the renin-angiotensin system until the increase in MAP restores perfusion pressure in the stenotic kidney and, consequently, Ang II release and hemodynamic conditions, with the exception of a sustained increase in peripheral vascular resistance and MAP. Lever²⁰ suggested that an initial increase in renin and Ang II might trigger a self-perpetuating mechanism that maintains systemic vasoconstriction despite relatively low circulating levels of Ang II. Similar autopotentiation also could account for the experimentally observed slow pressor responses to Ang II. However, the mechanisms responsible for this phenomenon remain undefined.

The significant correlation between PRA and PGF₂-isoprostanes observed during the early phase of RVH in the present study supports a link between the renin-angiotensin system and oxidation-mediated pathways.²¹ Ang II is a known stimulus for generation of reactive oxygen species,²² which may reduce the bioavailability of nitric oxide and produce isoprostanes through oxidation of arachidonic acid.⁸ However, in contrast to its early phase, during the chronic stage of RVH, PRA normalized and no longer correlated with either isoprostanes or MAP. Remarkably, plasma levels of PGF₂-isoprostanes remained elevated and continued to parallel the increase in MAP. In this setting, an increase in isoprostanes possibly could be achieved when bioavailability of nitric oxide is concurrently decreased or MAP simultaneously elevated, thereby constituting a powerful mechanism that potentially could augment vascular sensitivity to Ang II. This is underscored by our recent suggestion that enhanced vasoconstriction to low levels of Ang II could also result from a cascade of events related to increased oxidative stress.² Furthermore, activation of the tissue (rather than systemic) renin-angiotensin system may also contribute to a pro-oxidant shift in this setting. Nevertheless, hypertension per se might induce release of reactive oxygen species^{23 24} that could modulate a vicious cycle of several interdependent participants, and the present study cannot exclude the possibility that PGF₂-isoprostane formation resulted from increased MAP rather than Ang II.

Because both increased Ang II generation and ischemia promote formation of oxygen radicals,²⁵ oxidation-sensitive mechanisms could have been activated mainly in the stenotic kidney. However, as opposed to renal-vein PRA, PGF₂-isoprostanes levels did not lateralize to the side of the stenotic kidney at any experimental period and were in fact more increased in the contralateral renal vein at 10 weeks of RVH. Hence, activation of these pathophysiological mechanisms could have taken place in both kidneys, in the systemic vasculature, or elsewhere. Furthermore, tissue measurements also argued against the stenotic kidney as the sole locus of increased oxidative stress, because both kidneys showed a decrease of endogenous radical scavengers, as can be observed in various forms of renal injury.^{26 27}

Interestingly, the latter findings suggest a potential role for activation of redox-sensitive mechanisms not only in sustaining RVH, but also in evolving ischemic and hypertensive renal injury. Increased generation of reactive oxygen species is involved in the pathogenesis of various forms of renal dysfunction and damage^{14 28} and is one of the proposed mechanisms of Ang II–induced tissue damage.²⁹ Ang II–driven superoxide generation promotes mesangial hypertrophy and extracellular matrix production³⁰ and may cause membrane lipid oxidation and disruption of the structural integrity and capacity for cell transport and energy production.³¹ Activation of growth factors and cytokines^{32 33} and the mitogen-activated protein kinase/extracellular-regulated kinase cascade,³⁴ may also play a role in the mechanism of intrarenal action of Ang II and reactive oxygen species.

In summary, we observed that in the early phase of RVH, an increase in PRA and MAP was associated with increased systemic oxidation, which continued to parallel and could have potentially mediated sustenance of MAP when systemic PRA later declined. Further studies will be needed to determine whether these factors are causally related to sustaining RVH. Oxidation-sensitive mechanisms were also activated in the tissue and may conceivably play a role in progression of ischemic and hypertensive renal injury observed in renal artery stenosis.

	Acknowledgments

 
The present study was supported by grant Nos. HL-16496 and HL-03621 from the National Institutes of Health to the Mayo Foundation and by grant ISNIH 99.56980 (C.N.). The authors are grateful to Drs Yang Lee and Filomena de Nigris for their skillful technical assistance.

Received October 24, 2000; first decision December 11, 2000; accepted December 18, 2000.

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				M. Li, X. Dai, S. Watts, D. Kreulen, and G. Fink Increased superoxide levels in ganglia and sympathoexcitation are involved in sarafotoxin 6c-induced hypertension Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1546 - R1554. [Abstract] [Full Text] [PDF]

				G. J Dubel and T. P Murphy The role of percutaneous revascularization for renal artery stenosis Vascular Medicine, May 1, 2008; 13(2): 141 - 156. [Abstract] [PDF]

				S. C. Textor Atherosclerotic Renal Artery Stenosis: Overtreated but Underrated? J. Am. Soc. Nephrol., April 1, 2008; 19(4): 656 - 659. [Abstract] [Full Text] [PDF]

				J. L. Garvin and N. J. Hong Cellular Stretch Increases Superoxide Production in the Thick Ascending Limb Hypertension, February 1, 2008; 51(2): 488 - 493. [Abstract] [Full Text] [PDF]

				X.-Y. Zhu, E. Daghini, A. R. Chade, C. Napoli, E. L. Ritman, A. Lerman, and L. O. Lerman Simvastatin Prevents Coronary Microvascular Remodeling in Renovascular Hypertensive Pigs J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1209 - 1217. [Abstract] [Full Text] [PDF]

				N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]

				R. Olszanecki, R. Rezzani, S. Omura, D. E. Stec, L. Rodella, F. T. Botros, A. I. Goodman, G. Drummond, and N. G. Abraham Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway Am J Physiol Renal Physiol, January 1, 2007; 292(1): F148 - F157. [Abstract] [Full Text] [PDF]

				A. Spirou, E. Rizos, E. N. Liberopoulos, N. Kolaitis, A. Achimastos, A. D. Tselepis, and M. Elisaf Effect of Barnidipine on Blood Pressure and Serum Metabolic Parameters in Patients With Essential Hypertension: A Pilot Study Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2006; 11(4): 256 - 261. [Abstract] [PDF]

				A. R. Chade, J. D. Krier, S. C. Textor, A. Lerman, and L. O. Lerman Endothelin-A Receptor Blockade Improves Renal Microvascular Architecture and Function in Experimental Hypercholesterolemia J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3394 - 3403. [Abstract] [Full Text] [PDF]

				A. Kramer, M. van den Hoven, A. Rops, T. Wijnhoven, L. van den Heuvel, J. Lensen, T. van Kuppevelt, H. van Goor, J. van der Vlag, G. Navis, et al. Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2513 - 2520. [Abstract] [Full Text] [PDF]

				G. B. Silva, P. A. Ortiz, N. J. Hong, and J. L. Garvin Superoxide Stimulates NaCl Absorption in the Thick Ascending Limb Via Activation of Protein Kinase C Hypertension, September 1, 2006; 48(3): 467 - 472. [Abstract] [Full Text] [PDF]

				X.-Y. Zhu, E. Daghini, A. R. Chade, M. Rodriguez-Porcel, C. Napoli, A. Lerman, and L. O. Lerman Role of Oxidative Stress in Remodeling of the Myocardial Microcirculation in Hypertension Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1746 - 1752. [Abstract] [Full Text] [PDF]

				A. R. Chade, X. Zhu, O. P. Mushin, C. Napoli, A. Lerman, and L. O. Lerman Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia FASEB J, August 1, 2006; 20(10): 1706 - 1708. [Abstract] [Full Text] [PDF]

				R. J. Bolterman, M. C. Manriquez, M. C. O. Ruiz, L. A. Juncos, and J. C. Romero Effects of Captopril on the Renin Angiotensin System, Oxidative Stress, and Endothelin in Normal and Hypertensive Rats Hypertension, October 1, 2005; 46(4): 943 - 947. [Abstract] [Full Text] [PDF]

				A. R. Chade, O. P. Mushin, X. Zhu, M. Rodriguez-Porcel, J. P. Grande, S. C. Textor, A. Lerman, and L. O. Lerman Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia Hypertension, October 1, 2005; 46(4): 772 - 779. [Abstract] [Full Text] [PDF]

				V. D. Garovic and S. C. Textor Renovascular Hypertension and Ischemic Nephropathy Circulation, August 30, 2005; 112(9): 1362 - 1374. [Full Text] [PDF]

				R. de Silva, N. P. Nikitin, S. Bhandari, A. Nicholson, A. L. Clark, and J. G.F. Cleland Atherosclerotic renovascular disease in chronic heart failure: should we intervene? Eur. Heart J., August 2, 2005; 26(16): 1596 - 1605. [Abstract] [Full Text] [PDF]

				J. Herrmann, S. Samee, A. Chade, M. R. Porcel, L. O. Lerman, and A. Lerman Differential Effect of Experimental Hypertension and Hypercholesterolemia on Adventitial Remodeling Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 447 - 453. [Abstract] [Full Text] [PDF]

				X.-Y. Zhu, A. R. Chade, M. Rodriguez-Porcel, M. D. Bentley, E. L. Ritman, A. Lerman, and L. O. Lerman Cortical Microvascular Remodeling in the Stenotic Kidney: Role of Increased Oxidative Stress Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1854 - 1859. [Abstract] [Full Text] [PDF]

				S. C. Textor Ischemic Nephropathy: Where Are We Now? J. Am. Soc. Nephrol., August 1, 2004; 15(8): 1974 - 1982. [Abstract] [Full Text] [PDF]

				M. Varela, M. Herrera, and J. L. Garvin Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O2- and is diminished by a high-salt diet Am J Physiol Renal Physiol, August 1, 2004; 287(2): F224 - F230. [Abstract] [Full Text] [PDF]

				A. R. Chade, J. D. Krier, M. Rodriguez-Porcel, J. F. Breen, M. A. McKusick, A. Lerman, and L. O. Lerman Comparison of acute and chronic antioxidant interventions in experimental renovascular disease Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1079 - F1086. [Abstract] [Full Text] [PDF]

				A. R. Chade, M. Rodriguez-Porcel, J. Herrmann, X. Zhu, J. P. Grande, C. Napoli, A. Lerman, and L. O. Lerman Antioxidant Intervention Blunts Renal Injury in Experimental Renovascular Disease J. Am. Soc. Nephrol., April 1, 2004; 15(4): 958 - 966. [Abstract] [Full Text] [PDF]

				M. Galinanes and A. G Fowler Role of clinical pathologies in myocardial injury following ischaemia and reperfusion Cardiovasc Res, February 15, 2004; 61(3): 512 - 521. [Abstract] [Full Text] [PDF]

				M. V. Ullmann, M. Gorenflo, B. Rondelet, F. Kerbaul, S. Motte, S. Brimioulle, K. McEntee, P. Wauthy, R. Naeije, R. v. Beneden, et al. Bosentan and Overcirculation-Induced Experimental Pulmonary Arterial Hypertension * Response Circulation, December 9, 2003; 108 (23): e157 - e157. [Full Text] [PDF]

				R. Wolk, A. S.M. Shamsuzzaman, and V. K. Somers Obesity, Sleep Apnea, and Hypertension Hypertension, December 1, 2003; 42(6): 1067 - 1074. [Abstract] [Full Text] [PDF]

				E. Ritz and V. Haxsen Angiotensin II and Oxidative Stress: An Unholy Alliance J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2985 - 2987. [Full Text] [PDF]

				M. H. Sedeek, M. T. Llinas, H. Drummond, L. Fortepiani, S. R. Abram, B. T. Alexander, J. F. Reckelhoff, and J. P. Granger Role of Reactive Oxygen Species in Endothelin-Induced Hypertension Hypertension, October 1, 2003; 42(4): 806 - 810. [Abstract] [Full Text] [PDF]

				A. R. Chade, M. Rodriguez-Porcel, J. Herrmann, J. D. Krier, X. Zhu, A. Lerman, and L. O. Lerman Beneficial Effects of Antioxidant Vitamins on the Stenotic Kidney Hypertension, October 1, 2003; 42(4): 605 - 612. [Abstract] [Full Text] [PDF]

				J.-M. Li and A. M. Shah ROS Generation by Nonphagocytic NADPH Oxidase: Potential Relevance in Diabetic Nephropathy J. Am. Soc. Nephrol., August 1, 2003; 14(90003): S221 - 226. [Abstract] [Full Text] [PDF]

				A. R. Chade, M. Rodriguez-Porcel, J. P. Grande, X. Zhu, V. Sica, C. Napoli, T. Sawamura, S. C. Textor, A. Lerman, and L. O. Lerman Mechanisms of Renal Structural Alterations in Combined Hypercholesterolemia and Renal Artery Stenosis Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1295 - 1301. [Abstract] [Full Text] [PDF]

				T. Chabrashvili, C. Kitiyakara, J. Blau, A. Karber, S. Aslam, W. J. Welch, and C. S. Wilcox Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R117 - R124. [Abstract] [Full Text] [PDF]

				A. Makino, M. M. Skelton, A.-P. Zou, and A. W. Cowley Jr Increased Renal Medullary H2O2 Leads to Hypertension Hypertension, July 1, 2003; 42(1): 25 - 30. [Abstract] [Full Text] [PDF]

				M. Rodriguez-Porcel, L. O. Lerman, J. Herrmann, T. Sawamura, C. Napoli, and A. Lerman Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Coronary Endothelial Function Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 885 - 891. [Abstract] [Full Text] [PDF]

				J. Redon, M. R. Oliva, C. Tormos, V. Giner, J. Chaves, A. Iradi, and G. T. Saez Antioxidant Activities and Oxidative Stress Byproducts in Human Hypertension Hypertension, May 1, 2003; 41(5): 1096 - 1101. [Abstract] [Full Text] [PDF]

				S. H. Wilson, A. R. Chade, A. Feldstein, T. Sawamura, C. Napoli, A. Lerman, and L. O. Lerman Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia Nephrol. Dial. Transplant., April 1, 2003; 18(4): 703 - 709. [Abstract] [Full Text] [PDF]

				J. F. Reckelhoff and J. C. Romero Role of oxidative stress in angiotensin-induced hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R893 - R912. [Abstract] [Full Text] [PDF]

				M. Rodriguez-Porcel, A. Lerman, J. Herrmann, R. S. Schwartz, T. Sawamura, M. Condorelli, C. Napoli, and L. O. Lerman Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature Cardiovasc Res, April 1, 2003; 58(1): 213 - 221. [Abstract] [Full Text] [PDF]

				W. J. Welch, M. Mendonca, S. Aslam, and C. S. Wilcox Roles of Oxidative Stress and AT1 Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney Hypertension, March 1, 2003; 41(3): 692 - 696. [Abstract] [Full Text] [PDF]

				K. M. Hoagland, K. G. Maier, and R. J. Roman Contributions of 20-HETE to the Antihypertensive Effects of Tempol in Dahl Salt-Sensitive Rats Hypertension, March 1, 2003; 41(3): 697 - 702. [Abstract] [Full Text] [PDF]

				P. Minuz, P. Patrignani, S. Gaino, M. Degan, L. Menapace, R. Tommasoli, F. Seta, M. L. Capone, S. Tacconelli, S. Palatresi, et al. Increased Oxidative Stress and Platelet Activation in Patients With Hypertension and Renovascular Disease Circulation, November 26, 2002; 106(22): 2800 - 2805. [Abstract] [Full Text] [PDF]

				S. C. Textor Progressive Hypertension in a Patient With "Incidental" Renal Artery Stenosis Hypertension, November 1, 2002; 40(5): 595 - 600. [Full Text] [PDF]

				A. R. Chade, M. Rodriguez-Porcel, J. P. Grande, J. D. Krier, A. Lerman, J. C. Romero, C. Napoli, and L. O. Lerman Distinct Renal Injury in Early Atherosclerosis and Renovascular Disease Circulation, August 27, 2002; 106(9): 1165 - 1171. [Abstract] [Full Text] [PDF]

				J. D. Krier, M. Rodriguez-Porcel, P. J. M. Best, J. C. Romero, A. Lerman, and L. O. Lerman Vascular responses in vivo to 8-epi PGF2alpha in normal and hypercholesterolemic pigs Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R303 - R308. [Abstract] [Full Text] [PDF]

				Y. Higashi, S. Sasaki, K. Nakagawa, H. Matsuura, T. Oshima, and K. Chayama Endothelial Function and Oxidative Stress in Renovascular Hypertension N. Engl. J. Med., June 20, 2002; 346(25): 1954 - 1962. [Abstract] [Full Text] [PDF]

				J. R. Sowers Hypertension, Angiotensin II, and Oxidative Stress N. Engl. J. Med., June 20, 2002; 346(25): 1999 - 2001. [Full Text] [PDF]

				J. M. Hodgson, K. D. Croft, T. A. Mori, V. Burke, L. J. Beilin, and I. B. Puddey Regular Ingestion of Tea Does Not Inhibit In Vivo Lipid Peroxidation in Humans J. Nutr., January 1, 2002; 132(1): 55 - 58. [Abstract] [Full Text] [PDF]

				J. M. STULAK, A. LERMAN, M. R. PORCEL, J. A. CACCITOLO, J. C. ROMERO, H. V. SCHAFF, C. NAPOLI, and L. O. LERMAN Renal Vascular Function in Hypercholesterolemia Is Preserved by Chronic Antioxidant Supplementation J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1882 - 1891. [Abstract] [Full Text] [PDF]

				L. O. Lerman and M. Rodriguez-Porcel Functional Assessment of the Circulation of the Single Kidney Hypertension, September 1, 2001; 38(3): 625 - 629. [Abstract] [Full Text] [PDF]

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