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Hypertension. Author manuscript; available in PMC 2009 February 1. Published in final edited form as: Hypertension. 2008 August; 52(2): 256–263. Published online 2008 June 9. doi: 10.1161/HYPERTENSIONAHA.108.112706. PMCID: PMC2562771 NIHMSID: NIHMS52784 Copyright notice and Disclaimer Role of inflammation in the development of renal damage and dysfunction in Angiotensin II-induced hypertension Tang-Dong Liao, Xiao-Ping Yang, Yun-He Liu, Edward G. Shesely, Maria A. Cavasin, William A. Kuziel, Patrick J. Pagano, and Oscar A. Carretero Tang-Dong Liao, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Contributor Information. Correspondence to: Oscar A. Carretero, M.D.,.Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit MI 48202-2689, Phone: (313) 916-2103, Fax: (313) 916-1479, Email: ocarret1@hfhs.org

The publisher's final edited version of this article is available free at Hypertension.

See commentary "The flame that lights the fire: oxidative stress, inflammation, and renal damage in angiotensin II-induced hypertension." in Hypertension, volume 52 on page 205.

See other articles in PMC that cite the published article. Abstract Angiotensin II (Ang II)-induced hypertension is associated with an inflammatory response that may contribute to development of target organ damage. We tested the hypothesis that in Angiotensin II-induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in development of renal fibrosis, damage and dysfunction by causing: a) oxidative stress, b) macrophage infiltration, and c) cell proliferation. To test this hypothesis we used CCR2 knockout mice (CCR2−/−). The natural ligand of CCR2 is monocyte chemoattractant protein-1 (MCP-1), a chemokine important for macrophage recruitment and activation. CCR2−/− and age-matched wild-type (CCR2+/+) C57BL/6J mice were infused continuously with either Ang II (5.2 ng/10 g/min) or vehicle via osmotic mini-pumps for 2 or 4 weeks. Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in both strains of mice. However, in CCR2−/− mice with Ang II-induced hypertension, oxidative stress, macrophage infiltration, albuminuria and renal damage were significantly decreased and glomerular filtration rate was significantly higher than in CCR2+/+ mice. We concluded that in Ang II-induced hypertension, CCR2 activation plays an important role in development of hypertensive nephropathy via increased oxidative stress and inflammation. Keywords: inflammation, chemokine receptors, macrophage, reactive oxygen species, kidney diseases, albuminuria, fibrosis Introduction Hypertension is a major risk factor for renal nephrosclerosis; however, the mechanisms by which high blood pressure causes renal damage are not completely understood. Angiotensin II (Ang II), in addition to causing vasoconstriction, aldosterone release, and Na reabsorption by the nephron, also causes oxidative stress, inflammation, cell proliferation and, as a consequence, interstitial matrix accumulation and target organ damage. In the kidney, Ang II causes renal inflammation by stimulating superoxide formation and increasing chemokine release¹^–³. Chemokines are a family of low-molecular-weight cytokines that induce activation and migration of inflammatory cells and modulate functions of these cells. Monocyte chemoattractant protein (MCP-1) is one of the most prominent chemokines that regulates monocyte/macrophage infiltration. MCP-1 acts via its receptor, the CC chemokine receptor 2 (CCR2)⁴^,⁵. In mice lacking CCR2 (CCR2−/−), Ang II-induced vascular inflammation and remodeling are significantly reduced⁶. In a unilateral ureteral obstruction model of renal fibrosis and inflammation, CCR2 blockade ameliorates fibrosis and macrophage infiltration⁷^,⁸. Although these studies suggest that MCP-1/CCR2 activation, via macrophage infiltration, plays a crucial role in development of vascular and renal damage, it is unknown whether it contributes to renal damage and dysfunction in hypertension. Here we test the hypothesis that in Ang II-induced hypertension, CCR2 activation plays an important role in the development of renal fibrosis, damage and dysfunction by causing: a) oxidative stress, b) macrophage infiltration, and c) cell proliferation. To test this hypothesis we used CCR2 knockout mice (CCR2−/−) with Ang II-induced hypertension. Methods Male 12–14 week old homozygote CCR2−/− mice with a C57BL/6J genetic background (maintained in our mutant core facility), and matched male C57BL/6J, CCR2+/+ (Jackson Lab, Bar Harbor, Maine), were used in this study. All animal procedures, care, and housing were in accordance with guidelines of the Institutional Animal Care and Use Committee (IACUC) of Henry Ford Hospital. Ang II-induced hypertension Hypertension was induced by Ang II infusion via osmotic minipump (Alzet). Briefly, mice were anesthetized with sodium pentobarbital (50 mg/kg IP). Ang II was dissolved in 0.01N acetic acid saline solution to prevent it from attaching to the pump wall. Using sterile technique, mini pumps were placed subcutaneously in the intrascapular area to deliver Ang II at a dose of 5.2ng/10g/min. Vehicle groups were given 0.01N acetic acid saline solution. Prior to minipump implantation, mice were trained daily for 7 days to have systolic blood pressure (SBP) determined with a computerized tail-cuff system (BP 2000, Visitech)⁹. SBP was measured weekly. Three sets of 10 measurements were made for each recording. Experimental groups CCR2−/− and age-matched CCR2+/+ mice were randomly divided into four groups (11–15 mice per group): 1) CCR2+/+ plus vehicle, 2) CCR2−/−plus vehicle, 3) CCR2+/+ plus Ang II, and 4) CCR2−/− plus Ang II. After 4 weeks of Ang II or vehicle infusion, the mice were placed in metabolic cages for 24 hr urine collection. Volume was recorded and albumin measured using a commercially available enzyme-linked immunosorbent assay kit (ELISA; Alpha Diagnostic International, TX). Small groups of mice (n=5 per group) were studied after 2 weeks of Ang II-infusion. Since they did not yet have a significant renal disease, they were only used to determine macrophage infiltration and cell proliferation. Glomerular filtration rate (GFR) GFR was measured as previously described using fluorescein isothiocyanate label inulin (FITC-inulin, Sigma) ¹⁰. Briefly, FITC-inulin was injected as a bolus at 3 μl/g bw (body weight) and followed immediately by constant infusion of 0.15 μl/min/g bw. Following a 30 minute stabilization period, urine was collected for 30 minutes with a 100μl blood sample taken before and after urinary collection. Samples of FITC-inulin standards, plasma and diluted urine were individually transferred to a 96-well black microplate in triplicate and mixed with 10 mM HEPES buffer (N-(2-hydroxyethyl) piperazine-N′-(2-ethanesulfonic acid), pH 7.4). Plates were read with a micro-plate fluorescence reader (Labsystems Fluoroskan II) at excitation 485 nm, emission 538 nm. GFR was calculated using the following formula: GFR = (urine fluorescence value × urine volume/blood fluorescence value)/collection time. GFR was corrected by kidney weight (kw) with units expressed as fl/min/100 mg of kidney weight. Immunohistochemistry staining for macrophage and proliferated cells Paraffin-embedded sections (6 μm) were deparafinized and endogenous peroxidase activity was blocked using 0.3% hydrogen peroxide. The antigens were unmasked by microwave heat-induced epitope retrieval method in citrate acid buffer (pH 6.0). Nonspecific binding was blocked with 5% normal rabbit serum, then primary monoclonal antibodies; rat anti-mouse to F4/80 antigen, macrophage marker (clone: A3-1, 1:50, AbD SEROTEC)¹¹, or cell proliferation marker (monoclonal Ki-67 antibody, clone: TEC-3, 1:50 DAKO)¹²; were applied and incubated overnight at 4° C. Then the sections were incubated with secondary biotinylated antibody (rabbit anti-rat IgG). Immunoreactivity was detected with an ABC kit (Vectastain Elit e ABC peroxidase kit, Vector Lab) and visualized by 3-amino-9-ethylcarbazole solution (AEC, Zymed Lab). PBS buffer alone and nonspecific purified rat anti-mouse IgG (AbD Serotec) were used as a negative control and an isotype IgG control, respectively. Reddish-brown color was considered a positive stain. Sections were counterstained with hematoxylin. Images of 12 regions of the section were captured at 400 × magnifications using an inverted microscope (IX81, Olympus America, Center Valley, PA) with a digital camera (DP70, Olympus America, Center Valley, PA) and evaluated by a computerized image analysis system (Microsuite Biological imaging software, Olympus America, Center Valley, PA). F4/80 positive-staining cells were recognized as macrophages and those with KI-67 positive staining were counted as proliferating cells. Macrophages and Ki-67 positive cells are expressed as number of cells/mm². Immunohistochemistry staining and semi quantitative analysis for nitrotyrosine Transverse kidney sections were frozen, cut into 6 μm slices, and used for immunostaining of 3-nitrotyrosine, a marker for oxidative stress. A monoclonal antibody to 3-nitrotyrosine was used as primary antibody (clone: 1A6, 1:100, Millipore, Billerica, MA). The detection method was similar to that used for macrophage immunohistochemistry, except slices were fixed with cool acetone for frozen sections. For each slice, 24 images from the renal cortex were taken at ×400 magnification. Area and intensity of positive staining were scored separately by 3 independent observers unaware of treatment allocation. Area of positive staining was scored from 0 to 3 as follows: 0, no visible area; 1, small area; 2, medium area; and 3, large area. Intensity of positive staining was also scored from 0 to 3: 0, no visible staining; 1, faint staining; 2, moderate staining; and 3, strong staining. Western blot of NADPH oxidase gp91^phox in the kidney Eight fg protein from kidney cortex extracts were subjected to 10% SDS-PAGE under reducing conditions. Proteins were transferred to a nitrocellulose membrane. A monoclonal antibody against NADPH oxidase gp91^phox was used as primary antibody (supplied by Mark T Quinn, Ph.D., Montana State University). Signals were revealed with chemiluminescence (ECL kit, Chemicon) and visualized by autoradiography. Membranes were then stripped (Pierce) and reprobed with β-actin (polyclonal antibody, sc-1616, 1:1000, Santa Cruz) to verify equal loading. Bands’ optical density was quantified with a bioscanner and expressed as ratio of gp91^phox to β-actin. The positive band of gp91^phox was at molecular weight of 58 kDa and β-actin was at 43 kDa. Glomerular matrix The glomerular matrix was evaluated by periodic acid-Schiff staining (PAS, Sigma) as described previously¹³. Dark purple color in the glomerulus was recognized as extracellular matrix. Twenty-five to thirty glomeruli in each section were imaged at 400× magnification. Data were analyzed by computerized imaging software (Microsuite Biological imaging software, Olympus America, Center Valley, PA). The glomerular matrix was expressed as percentage of glomerular area. Renal cortex collagen determination by hydroxyproline assay Collagen content of kidney cortex tissue was determined using the hydroxyproline method as described previously¹⁴. A piece of the kidney cortex was dried, weighed, homogenized and then hydrolyzed with 6 N HCl for 18 hr at 110°C. Hydroxyproline content was determined using a colorimetric assay and a standard curve of 0 to 10 μg hydroxyproline. Data were expressed as fg collagen per mg dry weight, assuming that collagen contains an average of 13.5% hydroxyproline¹⁵. Data Analysis Data are expressed as mean ± SEM. SBP among the groups was compared using regression coefficient and average increasing rates. For the parameters including histological and immunohistochemical changes, glomerular matrix, renal collagen content, GFR and 24-hr urinary albumin, student’s two-sample t-test was used to compare differences between groups, either between strains with the same treatment or within one strain between different treatments. When multiple comparisons were performed, Hochberg’s step-up procedure was used to adjust the p values. Type one error rate was set at a=0.05. The differences were considered statistically significant when p < 0.05. Results SBP and left ventricle weight SBP before Ang II infusion was similar among groups. Ang II increased SBP in both CCR2+/+ and CCR2−/− strains (p < 0.001 vs vehicle within strain). The slope and average increase in SBP from basal were not statistically different between CCR2+/+ and CCR2−/− mice (Fig. 1

, upper panel). Ang II also increased left ventricular (LV) weight, and LV hypertrophy did not differ between CCR2+/+ and CCR2−/− mice (Fig. 1

, lower panel).

Figure 1 (A) Systolic blood pressure (SBP), and (B) Left ventricular weight (LVW) corrected for body weight (BW) in CCR2+/+ and CCR2−/− mice infused with either vehicle or Ang II. SBP was similar in vehicle groups of both strains. Ang II infusion (more ...) GFR and proteinuria GFR was similar in vehicle-treated groups of both strains. After 4 weeks of Ang II infusion, GFR decreased significantly in CCR2+/+ controls but remained unchanged in CCR2−/− mice (Fig. 2

, upper panel). Urinary albumin excretion was significantly increased in CCR2+/+ mice with Ang II-induced hypertension while it remained unchanged in CCR2−/− mice (Fig. 2

, lower panel).

Figure 2 (A) Glomerular filtration rate (GFR), and (B) urinary albumin in CCR2+/+ and CCR2−/− mice infused with either vehicle or Ang II. GFR was similar in vehicle groups of both strains. In CCR2+/+ with Ang II-induced hypertension, GFR was significantly (more ...) Macrophage infiltration Since inflammatory cell infiltration is an early response to Ang II, we studied macrophage infiltration as indicated by the number of F4/80-positive cells at 2- and 4-weeks after vehicle or Ang II infusion. In vehicle groups, there were few F4/80-positive positive cells in both strains. In the Ang II treated CCR2+/+ mice, F4/80-positive cells increased significantly at 2 and 4 weeks. The number of F4/80-positive cells was higher at 2 weeks compared to 4 weeks (Fig. 3

). In CCR2−/− mice, Ang II did not increase F4/80-positive cells neither at 2 or 4 weeks. F4/80-positive cells were mainly located in the tubulointerstitial space and glomerulus (Fig. 3

Figure 3 (A) Representative immunohistochemical staining for F4/80-positive cells (macrophages) in mice infused for 2 weeks with either vehicle or Ang II. Reddish-brown color in the cytoplasm indicates positive staining. Positive staining for macrophages was found (more ...) Nitrotyrosine and gp91^phox proteins expression 3-Nitrotyrosine staining, a marker of oxidative stress, was almost imperceptible in vehicle-treated groups of both strains. Ang II increased 3-nitrotyrosine staining (intensity and area) in both CCR2+/+ and CCR2−/−mice at 4 weeks; however the increase was significantly lower in CCR2−/− mice (Fig. 4

). gp91^phox protein expression also significantly increased in CCR2+/+ mice with Ang II infusion at 4 weeks, and this response was absent in CCR2−/− mice (Fig. 5

). Immunoblotting exhibited one positive band at 58 kDa. This molecular weight for gp91^phox was less than that reported for humans but similar to that in the mouse phagocyte gp91^phox clone¹⁶.

Figure 4 (A) Representative Immunohistochemical staining for nitrotyrosine (a peroxynitrite marker) in mice infused for 4 weeks with either vehicle or Ang II. Reddish-brown color was considered positive stain. Positive stain can be found in glomerulus and tubulointerstitial (more ...)

Figure 5 Renal tissue Western blot analysis of gp91^phox proteins (Nox2) in mice treated with either vehicle or Ang II. The upper panel shows representative Western blot for gp91^phox (58 kDa) and β-actin. The lower panel shows quantification of ratio of (more ...) Cell proliferation The number of Ki-67-positive cells was studied at 2- and 4-weeks. In CCR2+/+ mice, Ki-67-positive cells were significantly increased at both 2- and 4-weeks of Ang II infusion. In CCR2−/−, these increases were not present. Ki-67positive cells were found mainly in the glomerulus, tubule and tubulointerstial area (Fig. 6

Figure 6 (A) Representative immunohistochemical staining for Ki-67-positive cells (an indicator for cell proliferation) in mice infused for 4 weeks with vehicle or Ang II. Reddish-brown color in the nucleoli was considered positive. Positive cells were found in (more ...) Glomerular matrix and collagen content In the vehicle groups, glomerular matrix was similar between strains. After 4 weeks of Ang II infusion, glomerular matrix increased significantly in CCR2+/+ but not in CCR2−/− (Fig. 7

). In CCR2+/+, Ang II also increased renal collagen content measured using the hydroxyproline assay. Renal collagen content in CCR2−/− mice was unchanged after Ang II infusion (Fig. 8

Figure 7 (A) Representative periodic acid-Schiff (PAS) staining for glomerular matrix. Dark purple color in the glomerulus is extracellular matrix. Scale Bar = 25 μm. (B) Quantitative analysis of glomerular matrix area in mice treated with vehicle or Ang (more ...)

Figure 8 Collagen content, measured by hydroxyproline assay, in kidneys from mice treated with vehicle or Ang II. In CCR2+/+ with Ang II-induced hypertension, collagen content increased significantly (p < 0.025, vehicle vs Ang II), while in CCR2 −/−, (more ...) Discussion Our data demonstrate that Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in CCR2+/+ and CCR2−/− mice. However, in CCR2−/− mice with Ang II-induced hypertension, reactive oxygen species (ROS), macrophage infiltration, albuminuria and renal damage were significantly decreased and glomerular filtration rate was significantly higher than in CCR2+/+ mice. We concluded that in Ang II-induced hypertension, CCR2 activation plays an important role in development of hypertensive nephropathy via increased oxidative stress and inflammation. The most important ligand for the CCR2 is MCP-1 though CCR2 also binds MCP-2, MCP-3 and MCP-4¹⁷. Both Ang II and mechanical strain cause MCP-1 expression in vascular cells¹⁸^,¹⁹. MCP-1 plasma concentrations in normotensive CCR2+/+ and CCR2−/− mice are similar. Ang II infusion for 28 days increased plasma MCP-1 concentrations in both strains however in CCR2−/− mice the increase was significantly greater compared to CCR2+/+ mice⁶. Thus it is possible that in our study, Ang II either directly or via elevation of blood pressure caused MCP-1 release and CCR2 activation, resulting in ROS generation, macrophage infiltration (inflammation), cell proliferation and subsequent development of renal fibrosis and damage. Since both mouse strains developed similar degrees of hypertension and left ventricular hypertrophy but the severity of renal damage was significantly different, it could be assumed that high blood pressure itself is not responsible for renal damage. However, it could be that high blood pressure acts via mechanotransduction, causing MCP-1 release and CCR2 receptor activation, inflammation and renal damage. Similarly, it has been reported that Ang II infusion for 28 days causes similar degrees of hypertension and left ventricular hypertrophy in CCR2+/+ and CCR2−/− mice, however vascular inflammation and remodeling are significantly more severe in CCR2+/+ mice⁶. This study and ours suggest that in the absence of the CCR2 Ang II-induced hypertension causes less vascular and renal damage. However, it is possible that in a more chronic model of hypertension, renal damage occurs independent of CCR2 activation. Ang II, in addition to vasoactive and hemodynamic effects, can also act directly as a growth factor and proinflammatory cytokine²⁰^–²⁴. In our study, Ang II-induced hypertension showed increased renal ROS generation in CCR2+/+ mice, and this effect was significantly decreased in the absence of the CCR2 receptor. We assessed ROS generation by immunostaining of 3-nitrotyrosine, a peroxynitrite marker. Ang II administration increased both intensity and area of positive 3-trotyrosine immunostaining in kidneys of CCR2+/+ but not CCR2−/− mice. Nitrotyrosine staining was mainly in the glomerular area and some in the tubulointerstitial area and vessel walls. We also assessed the potential for ROS generation by measuring gp91phox, the main membrane component of the NADPH oxidase complex found in macrophages and various renal cells. We found that gp91phox expression was significantly increased in CCR2+/+, but this increase was not present in CCR2−/−. The present study supports the hypothesis that in Ang II-induced hypertension, CCR2 receptor activation participates in development of oxidative stress and inflammation and development of renal fibrosis and disease²⁵. Inflammation itself also increases oxidative stress²⁶. Thus, Ang II could cause oxidative stress directly by stimulating NADPH oxidase in renal tissue as well as by increasing macrophage infiltration in the kidney²⁷^–²⁹. Oxidative stress has also been implicated in the pathogenesis of Ang II-induced hypertension³⁰^–³³. However, in our study blood pressure was similar in CCR2+/+ and CCR2−/− mice, despite the observation that only the former had a significant increase in oxidative stress. Thus, our study does not support the hypothesis that oxidative stress participates in chronic elevation of blood pressure during Ang II infusion. Similar dissociation between oxidative stress and development of hypertension, especially at chronic stages, has been reported by Raij et al³⁴ and by Touyz et al³⁵. In our study, Ang II-induced hypertension increased renal macrophage infiltration in CCR2+/+ but not CCR2−/− mice, indicating that macrophage infiltration is mediated by CCR2 receptor activation. Similar to other studies, we found that macrophage infiltration was higher at 2- than at 4-weeks after Ang II infusion began³⁶^,³⁷. Macrophages were found mainly in the tubulointerstitial space, and to a lesser extent in the glomerulus, suggesting that infiltrated macrophages in the kidney may affect both tubular and glomerular cells. Macrophages, by their destructive potential and ability to secrete regulators of neighboring cells, contribute to renal and vascular damage in Ang II induced hypertension³⁸^,³⁹. We also observed that in Ang II-induced hypertension there is an increase in renal cell proliferation. Mesangial cells and interstitial fibroblasts are the major cells involved in renal fibrosis. They proliferate in response to macrophage-derived cytokines such as IL-1, IL-2 and TNF-α⁴⁰^,⁴¹. Also, Ang II, directly and/or via ROS generation, could increase renal cell proliferation⁴²^,⁴³. It has been shown that the number of mesangial cells and interstitial fibroblasts correlates with renal fibrosis and dysfunction⁴⁴. We found proliferating cells in the glomerular and tubulointerstitial area in CCR2+/+ with Ang II-induced hypertension. It could be that mesangial cells and fibroblast proliferation participate in development of renal fibrosis²¹^,⁴². Renal fibrosis was evaluated by measuring renal cortex collagen and glomerular matrix. Ang II administration increased renal cortex fibrosis and glomerular matrix significantly in CCR2+/+ but not in CCR2−/− mice. These results agree with other studies stating that CCR2 blockade and/or decreasing macrophage infiltration ameliorated progressive renal fibrosis in unilateral ureteral obstruction and type 2 diabetic db/db mice⁷^,⁸^,⁴⁵. Increased renal fibrosis in Ang II-induced hypertension may be related to augmented oxidative stress and macrophage infiltration and subsequent mesangial cell and fibroblast proliferation. In contrast, mice lacking CCR2 have less cell proliferation and better renal function. Decreased collagen synthesis in the cortex and extracellular matrix deposition in the glomerulus may help to maintain GFR. In summary, following Ang II administration, mice lacking CCR2 exhibit less: a) ROS generation, b) macrophage infiltration, c) cell proliferation, d) glomerular matrix, and e) collagen deposition in the kidney compared to CCR2+/+. Lower ROS generation and macrophage infiltration could lead to reduced injury to the glomerular filtration membrane and tubules, while lower extracellular matrix deposition and cell proliferation in the glomerulus are beneficial for preserving renal function. These results suggest that CCR2 plays an important role in development of renal injury and dysfunction, which are associated with ROS generation, macrophage infiltration, cell proliferation and extracellular matrix deposition. Perspectives Chronic hypertension is a major risk factor in development of renal nephrosclerosis and end stage renal disease. Hypertensive renal disease varies markedly between individuals with similar blood pressure; for example, it has been shown to be more common in African Americans than Caucasians. Also Dahl salt-sensitive rats have more severe renal damage than spontaneously hypertensive rats with similar blood pressure⁴⁶^–⁴⁸. These studies suggest that in addition to high blood pressure, other factors, including genetic characteristics, and inflammation participate in the pathogenesis of renal disease in hypertension⁴⁹^,⁵⁰. Our study provides experimental evidence that lack of CCR2 ameliorates renal inflammation injury and dysfunction induced by Ang II. These findings may lead to novel therapies directed at blockade of either MCP-1 or CCR2. Acknowledgments Sources of Funding: This work was supported by National Institutes of Health grants HL-28982(O.A.C.). Contributor Information Tang-Dong Liao, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Xiao-Ping Yang, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Yun-He Liu, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Edward G. Shesely, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Maria A. Cavasin, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; William A. Kuziel, PDL BioPharma, Inc., Fremont, CA 94555, USA; Patrick J. Pagano, Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Oscar A. 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