Published online before print July 16, 2007, doi: 10.1161/HYPERTENSIONAHA.107.093989
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2007;50:729.)
© 2007 American Heart Association, Inc.
XVIIth Scientific Meeting of the Inter-American Society of Hypertension |
Role of Renal Cortical Neovascularization in Experimental Hypercholesterolemia
From the Divisions of Nephrology and Hypertension (A.R.C., J.D.K., L.O.L.) and Cardiovascular Diseases (O.G., A.L., L.O.L.), Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn. Current address (A.R.C.): Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss.
Correspondence to Lilach O. Lerman, Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail Lerman.Lilach{at}Mayo.Edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Hypercholesterolemia induces renal inflammation and neovascularization, associated with renal endothelial dysfunction and injury. Neovascularization might conceivably represent a defense mechanism to sustain renal perfusion. Therefore, the present study was designed to test the hypothesis that preventing neovascularization using thalidomide, a potent anti-inflammatory and antiangiogenic agent, would impair basal renal hemodynamics in experimental hypercholesterolemia. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 weeks of hypercholesterolemia, hypercholesterolemia chronically supplemented with thalidomide (4 mg/kg per day), and normal controls. Renal microvascular architecture was then studied ex vivo using 3D microcomputed tomography imaging and inflammation, angiogenesis, and oxidative stress explored in renal tissue. The density of larger microvessels (200 to 500 µm) was selectively decreased in hypercholesterolemia plus thalidomide and accompanied by a decreased fraction of angiogenic, integrin ß3-positive microvessels (9.9%±0.9% versus 25.5%±1.7%; P<0.05 versus hypercholesterolemia), implying decreased angiogenic activity. Furthermore, thalidomide increased renal expression of endothelial NO synthase and decreased tumor necrosis factor-
and renal inflammation but did not decrease oxidative stress. Thalidomide also decreased basal renal blood flow and glomerular filtration rate but normalized the blunted renal hemodynamic responses in hypercholesterolemia. Attenuated inflammation and pathological angiogenesis achieved in hypercholesterolemia by thalidomide are accompanied by restoration of renovascular endothelial function but decreased basal renal hemodynamics. This study, therefore, suggests that neovascularization in the hypercholesterolemic kidney is a compensatory mechanism that sustains basal renal vascular function.
Key Words: kidney • thalidomide • hypercholesterolemia • microcirculation • inflammation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Hypercholesterolemia (HC) is present in >50% of the middle-aged adult US population1 and constitutes a risk factor for atherosclerosis.1,2 Notably, before the presence of overt plaques, lipid abnormalities can impair both the function and structure of large and small vessels of many types of vascular beds and can damage target organs.
Lipid abnormalities are frequently associated with renal disease3 and dysfunction4 and may trigger renal injury at an early stage. HC may increase renal oxidative stress, which may impair the function of the microvascular network (MV) by decreasing NO bioavailability and favoring vasoconstriction, endothelial dysfunction, inflammation, fibrosis, and tissue injury.5–7 Inflammation is involved in many forms of renal injury but may also trigger compensatory mechanisms to offset tissue injury. For example, increased oxidative stress and, to a lesser degree, inflammation, are considered the main mechanisms leading to vascular endothelial dysfunction. Furthermore, we have shown previously that diet-induced HC also results in renal MV proliferation,8 possibly because of renal inflammation. Proliferation of pathological and dysfunctional MV, showing decreased intercellular contact and increased permeability,9 may culminate in renal tissue injury and interstitial fibrosis.10 On the other hand, increased MV density can contribute to tissue perfusion but is not fully effective in HC because it was insufficient to preserve the endothelial function of the kidney.8,11 Therefore, the role of HC-induced inflammation and neovascularization in the kidney remained unclear.
Thalidomide is a racemic glutamic acid derivative with prominent antiangiogenic properties approved in the United States for erythema nodosum leprosum12 and multiple myeloma.13 In addition, its use in various inflammatory and oncologic conditions is under intense investigation. Indeed, growing evidence shows the anti-inflammatory effects of this drug achieved through downregulation of key cytokines, such as nuclear factor 
B, tumor necrosis factor (TNF)-,14–16 and interleukins. These factors are all highly expressed in the HC kidney and promote renal inflammation and MV endothelial dysfunction.17,18 The antiangiogenic and anti-inflammatory properties of thalidomide, therefore, provide the opportunity to study the role of renal neovascularization induced by inflammation in HC. Hence, the present study was designed to test the hypothesis that chronic thalidomide supplementation would attenuate intrarenal inflammation, decrease MV proliferation, and consequently impair the basal hemodynamics and function of the HC kidney.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The Institutional Animal Care and Use Committee approved all of the procedures. Twenty domestic pigs (50 to 60 kg) were studied after 12 weeks of normal control (n=7), a 2% HC (n=7)6,18–20 diet, and HC with oral supplementation with thalidomide at a standard dose ([HC+thal] 4 mg/kg per day, Celgene Co12; n=6 per group).
On the day of the in vivo studies, animals were anesthetized with a mixture of intramuscular telazol (5 mg/kg) and xylazine (2 mg/kg), intubated, and mechanically ventilated with room air. Anesthesia was maintained intravenously through an ear vein with a mixture of ketamine (0.2 mg/kg per minute) and xylazine (0.03 mg/kg per minute) in normal saline. Under sterile conditions and fluoroscopic guidance, via a neck cutdown, a pigtail catheter was placed in the superior vena cava and an 8F arterial catheter in the abdominal aorta above the renal arteries. Blood pressure was measured using the side arm of a carotid arterial sheath. In vivo electron-beam computed tomography (CT) flow studies were then performed to assess basal and challenged renal blood flow (RBF) and glomerular filtration rate (GFR). We have shown previously that, using electron-beam CT, we can obtain accurate, repeated, and noninvasive quantifications of RBF and GFR5,6,11,19,21–26 in the intact single kidney in vivo, allowing evaluation of renal and renovascular function. Briefly, a sequential acquisition of 40 consecutive scans followed a central venous injection of the contrast medium iopamidol (0.5 cc/kg per 2 seconds). These were repeated during suprarenal aortic infusion of acetylcholine (Ach, 5 µg/kg per minute) to test intrarenal MV endothelium-dependent responses. Blood samples were collected from the inferior vena cava for measurement of lipid profile (Roche Laboratories),6 oxidized low-density lipoprotein (LDL; Mercodia),24 and circulating TNF- (R&D Systems).27
The pigs were killed 3 days after completion of the in vivo studies (to allow elimination of contrast media and/or vasoactive agents) with a lethal intravenous dose of sodium pentobarbital (100 mg/kg, Sleepaway, Ft Dodge Laboratories, Inc). Kidneys were removed using a retroperitoneal incision and were immersed in Krebs’ solution containing heparin (10 U/mL) to prevent drying. A lobe of tissue was immersed in 10% buffered formalin (Sigma), and a segmental artery perfusing the intact end of the kidney was cannulated and prepared for micro-CT. This imaging technique permits assessment of the 3D pattern of MV structure in situ, providing powerful means for studying their spatial distribution and connectivity. We have shown the feasibility of studying renal architecture with micro-CT in experimental HC8,11 and renovascular disease.24,28 Another lobe of renal tissue was removed from 1 end of the kidney, shock-frozen in liquid nitrogen, and stored at –80°C.5–7,22–24
In vitro studies were then performed to assess the expression of proinflammatory, angiogenic, and fibrogenic factors in the kidney. Renal redox status was evaluated by assessing the in situ production of superoxide anion, detected by fluorescence microscopy using dihydroethidium,26 by the expression by Western blotting of the radical forming enzymes reduced nicotinamide-adenine dinucleotide phosphate–oxidase (p47phox and p67phox), xanthine oxidase, and uncoupled endothelial NO synthase (eNOS), the main sources of reactive oxygen species (ROS). Furthermore, the endogenous antioxidant activity was investigated by assessing the expression of CuZn superoxide dismutase (SOD), the predominant form of SOD in blood vessels,29 and the ratio of reduced/oxidized glutathione (Oxis Inc), as described previously.24,26,30 Western blotting and PCR were also used to assess renal protein and/or mRNA expression of TNF-, vascular endothelial growth factor (VEGF), plasminogen (Plg), and pre-pro endothelin (ET)-1 and its specific ET-A and ET-B receptors. Renal expression of Plg was used as a marker of vascular permeability31 that characterizes angiogenic MV. In addition, MV density and proliferation were assessed by micro-CT (see below) and by renal immunoreactivity for integrin ß3. Renal inflammation and angiogenic vessels were investigated in representative 5-µm–thick renal midhilar cross-sections (1 per animal) stained with CD-3 and integrin ß3, respectively.
Micro-CT
The kidney was perfused with a radio-opaque silicone polymer (Microfil MV122, Flow Tech, Inc) and scanned at 0.5° increments using a micro-CT scanner, as described previously.8,28,32 For details, see the online supplement, available at http://hyper.ahajournals.org.
Real-Time Quantitative PCR
To investigate the renal mRNA expression of eNOS, TNF-, pre-pro ET-1, ET-A, and ET-B, real-time PCR (DNA engine OPTICON, MJ Research) was performed using a SYBR Green JumpStart Taq ReadyMix kit (Sigma). Either human or porcine (when available) gene-specific sequences were used, as described previously.5,8,32 For details, see the online supplement.
Western Blotting
Standard blotting protocols were followed, as described previously.5,7,22–24 Intensities of the protein bands (1 per animal) were determined using densitometry, quantified, and averaged. For details, see the online supplement.
Immunohistochemistry
Staining was performed in 5 µm of either frozen (integrin ß3, Chemicon International, 1:80) or paraffin (CD-3, Cell Marque Corporation, 1:300) midhilar renal cross-sections following standard procedures.5,24 For details, see the online supplement.
Data Analysis
Electron-Beam CT Analysis
Manually traced regions of interest were selected in electron-beam CT images in the aorta, renal cortex, and medulla, and their densities were sampled over time. Time-density curves were generated and used to calculate single-kidney RBF and GFR using previously validated methods.5–7,19,21–24,26 For details, see the online supplement.
Micro-CT Analysis
3D volume images were reconstructed and analyzed with the Analyze software package (Biomedical Imaging Resource, Mayo Clinic) as described previously.8,24,28,32 For details, see the online supplement.
Renal Histology
Midhilar cross-sections of the kidney (1 per animal) were examined using a computer-aided image-analysis program (MetaMorph, Meta Imaging Series 6.3.2).5–7,22–24 For quantification of vessels expressing integrin ß3, all of the vessels were manually counted in each slide (1 per animal), and the fraction of integrin plus vessels per slide was calculated. For additional details, see the online supplement.
Statistical Analysis
Results are expressed as mean±SEM. Comparisons within groups were performed using paired Student’s t test and among groups using ANOVA, with the Bonferroni correction for multiple comparisons, followed by unpaired Student’s t test. Statistical significance was accepted for P
0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Body weight and mean arterial pressure were similar among the groups, whereas total and LDL cholesterol, as well as circulating oxidized LDL levels, were similarly elevated in HC and HC+thal animals compared with normal animals (Table).
|
MV 3D Architecture and Angiogenic Factors
The density of larger MV (200 to 500 µm) was similar in normal and HC but selectively decreased in HC+thal animals (Figure 1). This was accompanied by decreased renal expression of VEGF and Plg, as well as a reduction in the fraction of integrin ß3-positive vessels compared with untreated HC (Figure 1), implying a reduction in renal angiogenic activity. As we have shown before,8 the HC kidney showed a significant increase in the density of smaller MV (<200 µm) compared with normal, which was interestingly accentuated in HC+thal (Figure 1). The reciprocal increase in the small MV density resulted in the transmural spatial MV density that was overall similarly increased in HC and HC+thal compared with normal (81.0±12.0, 110.8±20.1, and 48.5±11.9 MV/cm2, respectively; P<0.05 versus normal). However, because of the increased density of small vessels relative to large MV, the average diameter and vascular volume fraction of cortical MV were significantly reduced in HC+thal compared with normal kidneys (Figure 1).
|
P<0.05 vs HC.
Renal Inflammation
Circulating levels and renal expression of proinflammatory TNF-, and renal CD3+ cells were increased in HC but normalized in thalidomide-treated animals, indicating attenuation in renal inflammation (Figure 2).
|
MV and Renal Function
Basal RBF and GFR in HC were not different from normal but were reduced in HC+thal pigs (Table). Infusion of Ach was not associated with a persistent change in blood pressure, as we have shown previously.6 The increase in RBF in response to Ach was blunted in HC (+6.4±8.4%; P value not significant versus baseline) but was significant in both normal and thalidomide-treated HC animals (+31.6±8.6% and +33.8±8.9%, respectively; P<0.05 versus baseline for both), whereas GFR responses to Ach were not different among the normal, HC, and HC+thal groups (+32.4±8.4%, +35.4±12.1%, and +43.5±8.9%, respectively; P<0.05 versus baseline for all; Figure 3). Notably, the blunted renal expression of eNOS in HC and the increased expression of the ET-A receptor were normalized in HC+thal kidneys (Figure 3), suggesting a vasodilator permissive milieu. However, the expressions of uncoupled eNOS, xanthine oxidase, and reduced nicotinamide-adenine dinucleotide phosphate–oxidase were increased in HC kidneys, and most were further elevated in HC+thal, suggesting the potential for increasing renal oxidative stress (Figure 4). In contrast, renal reduced/oxidized glutathione and CuZn SOD expression were also significantly increased in HC+thal compared with both normal and HC, implying augmented potential for ROS scavenging as well. Consequently, the overall abundance of ROS in the tissue (as reflected in dihydroethidium fluorescence) and index of oxidative stress were similarly elevated in HC and HC+thal compared with normal animals.
|
) and in response to Ach (
). Bottom, Renal protein and mRNA expression and quantification of eNOS (left) and pre-pro ET-1, ET-A, and ET-B receptors (right) in normal, HC, and HC+thal animal. Basal RBF and GFR were reduced in HC+thal. Blunted renovascular endothelial function in HC was restored after thalidomide treatment, accompanied by augmented renal eNOS and attenuated ET-A receptor expression. *P<0.05 vs baseline;
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study shows that a 12-week regimen of thalidomide supplementation significantly decreased renal inflammation and arrested MV proliferation in the HC kidney. These effects were accompanied by decreased RBF and GFR, suggesting that renal neovascularization in HC contributed to maintaining basal renal hemodynamics and vascular function. Nevertheless, despite lingering renal oxidative stress, thalidomide also improved endothelium-dependent MV function in HC, underscoring the contribution of inflammation to renal dysfunction.
The role of lipid abnormalities as a prominent risk factor for renal disease progression has been increasingly recognized,33 and deterioration of renal function is conversely also associated with and promotes alterations in lipid metabolism. We have shown previously that diet-induced HC led to a significant increase in oxidative stress and renal inflammation associated with renovascular endothelial dysfunction and MV proliferation and remodeling.5,6,18 Inflammation is a complex process involving changes in hemodynamics, vascular reactivity, and activation and migration of inflammatory cells.34 One of the defense mechanisms by which inflammation facilitates healing is formation of new vessels to sustain perfusion of ischemic or diseased tissues.35 Indeed, we have shown previously that the HC kidney exhibits neovascularization, possibly reflecting a compensatory mechanism to episodes of inadequate perfusion, although renovascular endothelial function remained attenuated in HC. Hence, the role of the neovessels in the HC kidney remained unclear.
Thalidomide is an immunomodulatory agent known not only for its anti-inflammatory actions but also for its capability for arresting angiogenesis.13 The mechanism of antiangiogenic activity of thalidomide may include decreasing cell migration36 or downregulation of proangiogenic factors such as VEGF.37 Accordingly, in the current study, the HC+thal kidney showed decreased expression of VEGF accompanied by a decrease in the density of large renal MV (between 200 and 500 µm in size) compared with both normal and HC animals. Intriguingly, however, whereas HC showed increased density of small MV (<200 µm) compared with controls, HC+thal animals showed a higher density of small MV. The smaller diameter, lower Plg expression (implying decreased vascular leakage31), and decreased abundance of integrin ß3-positive vessels in HC+thal supports the notion that the increased density of small MV in these animals was not because of angiogenic microvessels,38 which are characterized by increased permeability and larger diameter.39 Furthermore, MV endothelial function in vivo was importantly normalized in HC+thal kidneys. Hence, these smaller MVs in HC+thal might reflect recruitment of pre-existing MV to compensate for the regression of some of the upstream vasculature. This reciprocal increase in MV <200 µm resulted in an overall MV density that was similarly elevated in HC and HC+thal compared with normal animals. On the other hand, the selective decrease in larger MV by thalidomide may account for the reduced vascular volume fraction and thereby RBF and GFR, suggesting that those new vessels served to sustain basal renal perfusion in HC. Nevertheless, the blunted hemodynamic responses to endothelium-dependent challenge and increased MV permeability in HC (implying renovascular endothelial dysfunction) suggested that those angiogenic MVs in the HC kidney were dysfunctional. The unimpaired GFR response to Ach in HC underscores its regulation that may be different than that of vascular resistance.
The current study also shows that experimental HC upregulates both the systemic and renal levels of the proinflammatory mediator TNF-, which has been implicated in the pathogenesis of many inflammatory diseases of the kidney. TNF- is synthesized by resident glomerular cells in response to injury and by infiltrating macrophages and can promote renal dysfunction via direct cytotoxicity, vasoconstriction, and decreased RBF and by the recruitment of neutrophils and monocytes.40 Elevated TNF- can also decrease GFR by promoting glomerular fibrin deposition, cellular infiltration, and vasoconstriction and may induce the synthesis of other proinflammatory mediators.40 Importantly, thalidomide treatment significantly reduced both the circulating and renal protein and mRNA expressions of TNF- in HC and decreased infiltration of CD3+ cells, suggesting attenuated renal inflammation.
Increased abundance of superoxide anion is considered to be one of the main mechanisms mediating renal endothelial dysfunction. Nevertheless, inflammatory states may be associated with abnormal vascular function, likely as a result of downregulated eNOS and consequently decreased synthesis and availability of NO.41 The current study shows that the blunted renovascular endothelial function6 is accompanied by a decrease in both renal protein and mRNA expression of eNOS in the HC kidney. This might have been mediated by TNF-, which contributes to endothelial dysfunction by reducing the half-life of mRNA encoding for eNOS.42 Interestingly, thalidomide upregulated eNOS renal mRNA and protein expression, which may account for both MV recruitment and the improved RBF responses to Ach. Furthermore, increased TNF- in HC may have favored renal vasoconstriction by stimulating ET,43 and we have shown previously that diet-induced HC upregulates both renal ET-1 and its ET-A receptor.5,25 This study suggests that thalidomide treatment may also exert its effects by downregulating the ET-A receptor, an effect that may have, in turn, contributed to restore eNOS.18 Furthermore, downregulation of the ET-A receptor can offset the vasoconstrictor effects of TNF-.44 Hence, the enhanced vasodilator milieu in HC+thal may have increased recruitment of pre-existing MV that, in turn, had better endothelial function than angiogenic MV. Moreover, the improvement in endothelial function observed in the HC+thal kidney in the face of lingering oxidative stress re-enforces the important impact of inflammation on vascular architecture and function.45
In contrast to the improved endothelial function and decreased inflammation, the effects of thalidomide on oxidative stress could potentially be deleterious. Renal expression of both reduced nicotinamide-adenine dinucleotide phosphate oxidase and uncoupled-eNOS, which are known sources of ROS, was significantly increased in HC+thal compared not only with normal, but with HC animals as well, although renal expression of xanthine oxidase was similarly increased. ROS have a distinct constrictor effect on the afferent arteriole,46 which may also account for the lower RBF and GFR observed in HC+thal animals. However, thalidomide also augmented in the HC kidney the ratio of renal reduced/oxidized glutathione and the expression of CuZn SOD. Hence, in parallel with its pro-oxidant effects, thalidomide promoted renal ROS scavenging, which may explain why superoxide abundance in situ was not higher than in HC. Yet, the remaining ROS and oxidized LDL might have contributed to the decrease in basal RBF and GFR, because thalidomide has been suggested to exacerbate pre-existing renal impairment47 and might have potentially aggravated their vasoconstrictor effects.
Perspectives
The current study shows for the first time that chronic thalidomide treatment decreased renal inflammation and angiogenesis in HC, thereby restoring renovascular endothelial function but at the same time decreasing basal RBF and GFR. Interestingly, the early stages of renal inflammation and oxidative stress are promoted in HC without a concomitant increase in arterial pressure, possibly because of impaired tubular concentration mechanisms.20 Nonetheless, inflammation and oxidative stress could still eventually promote hypertension in HC and atherosclerotic patients and, thus, potentially thalidomide might indirectly blunt development of hypertension. In conclusion, these results demonstrate the dual role of inflammation as both a pathological process and defense mechanism during the evolution of renal injury in early atherosclerosis.
|
Acknowledgments |
|---|
Thalidomide was generously provided by Celgene Co.
Sources of Funding
This work was supported by National Institutes of Health grants HL-77131, DK073608, and EB 000305.
Disclosures
None.
|
Footnotes |
|---|
This paper was sent to Joey Granger, associate editor, for review by expert referees, editorial decision, and final disposition.
Received May 15, 2007; first decision May 31, 2007; accepted June 19, 2007.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, Ellis SG, Lincoff AM, Topol EJ. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003; 290: 898–904.
[Abstract/Free Full Text] - Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
[Free Full Text] - O’Hare AM, Glidden DV, Fox CS, Hsu CY. High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999–2000. Circulation. 2004; 109: 320–323.
[Abstract/Free Full Text] - Bax L, van der Graaf Y, Rabelink AJ, Algra A, Beutler JJ, Mali WP. Influence of atherosclerosis on age-related changes in renal size and function. Eur J Clin Invest. 2003; 33: 34–40.[CrossRef][Medline] [Order article via Infotrieve]
- Chade AR, Mushin OP, Zhu X, Rodriguez-Porcel M, Grande JP, Textor SC, Lerman A, Lerman LO. Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia. Hypertension. 2005; 46: 772–779.
[Abstract/Free Full Text] - Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC, Napoli C, Lerman LO. Distinct renal injury in early atherosclerosis and renovascular disease. Circulation. 2002; 106: 1165–1171.
[Abstract/Free Full Text] - Chade AR, Rodriguez-Porcel M, Grande JP, Zhu X, Sica V, Napoli C, Sawamura T, Textor SC, Lerman A, Lerman LO. Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis. Arterioscler Thromb Vasc Biol. 2003; 23: 1295–1301.
[Abstract/Free Full Text] - Chade AR, Bentley MD, Zhu X, Rodriguez-Porcel M, Niemeyer S, Amores-Arriaga B, Napoli C, Ritman EL, Lerman A, Lerman LO. Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs. J Am Soc Nephrol. 2004; 15: 1816–1825.
[Abstract/Free Full Text] - Henry PD, Cabello OA, Chen CH. Hypercholesterolemia and endothelial dysfunction. Curr Opin Lipidol. 1995; 6: 190–195.[Medline] [Order article via Infotrieve]
- Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, Wrenn SP, Narula J. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005; 25: 2054–2061.
[Abstract/Free Full Text] - Chade AR, Krier JD, Textor SC, Lerman A, Lerman LO. Endothelin-A receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia. J Am Soc Nephrol. 2006; 17: 3394–3403.
[Abstract/Free Full Text] - Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL. Clinical pharmacokinetics of thalidomide. Clin Pharmacokinet. 2004; 43: 311–327.[CrossRef][Medline] [Order article via Infotrieve]
- Sze DM, Brown R, Yang S, Ho PJ, Gibson J, Joshua D. The use of thalidomide in myeloma therapy as an effective anticancer drug. Curr Cancer Drug Targets. 2006; 6: 325–331.[CrossRef][Medline] [Order article via Infotrieve]
- Zhang N, Ahsan MH, Zhu L, Sambucetti LC, Purchio AF, West DB. NF-kappaB and not the MAPK signaling pathway regulates GADD45beta expression during acute inflammation. J Biol Chem. 2005; 280: 21400–21408.
[Abstract/Free Full Text] - Yasui K, Kobayashi N, Yamazaki T, Agematsu K. Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des. 2005; 11: 395–401.[CrossRef][Medline] [Order article via Infotrieve]
- Yagyu T, Kobayashi H, Matsuzaki H, Wakahara K, Kondo T, Kurita N, Sekino H, Inagaki K, Suzuki M, Kanayama N, Terao T. Thalidomide inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-kappaB activation. J Clin Endocrinol Metab. 2005; 90: 3017–3021.
[Abstract/Free Full Text] - Wilson SH, Chade AR, Feldstein A, Sawamura T, Napoli C, Lerman A, Lerman LO. Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia. Nephrol Dial Transplant. 2003; 18: 703–709.
[Abstract/Free Full Text] - Chade AR, Best PJ, Rodriguez-Porcel M, Herrmann J, Zhu X, Sawamura T, Napoli C, Lerman A, Lerman LO. Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia. Kidney Int. 2003; 64: 962–969.[CrossRef][Medline] [Order article via Infotrieve]
- Chade AR, Rodriguez-Porcel M, Rippentrop SJ, Lerman A, Lerman LO. Angiotensin II AT1 receptor blockade improves renal perfusion in hypercholesterolemia. Am J Hypertens. 2003; 16: 111–115.[CrossRef][Medline] [Order article via Infotrieve]
- Feldstein A, Krier JD, Sarafov MH, Lerman A, Best PJ, Wilson SH, Lerman LO. In vivo renal vascular and tubular function in experimental hypercholesterolemia. Hypertension. 1999; 34: 859–864.
[Abstract/Free Full Text] - Krier JD, Ritman EL, Bajzer Z, Romero JC, Lerman A, Lerman LO. Noninvasive measurement of concurrent single-kidney perfusion, glomerular filtration, and tubular function. Am J Physiol Renal Physiol. 2001; 281: F630–F638.
[Abstract/Free Full Text] - Chade AR, Rodriguez-Porcel M, Herrmann J, Krier JD, Zhu X, Lerman A, Lerman LO. Beneficial effects of antioxidant vitamins on the stenotic kidney. Hypertension. 2003; 42: 605–612.
[Abstract/Free Full Text] - Chade AR, Rodriguez-Porcel M, Herrmann J, Zhu X, Grande JP, Napoli C, Lerman A, Lerman LO. Antioxidant intervention blunts renal injury in experimental renovascular disease. J Am Soc Nephrol. 2004; 15: 958–966.
[Abstract/Free Full Text] - Chade AR, Zhu X, Mushin OP, Napoli C, Lerman A, Lerman LO. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. FASEB J. 2006; 20: 1706–1708.
[Abstract/Free Full Text] - Chade AR, Herrmann J, Zhu X, Krier JD, Lerman A, Lerman LO. Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia. J Am Soc Nephrol. 2005; 16: 1005–1012.
[Abstract/Free Full Text] - Chade AR, Krier JD, Rodriguez-Porcel M, Breen JF, McKusick MA, Lerman A, Lerman LO. Comparison of acute and chronic antioxidant interventions in experimental renovascular disease. Am J Physiol Renal Physiol. 2004; 286: F1079–F1086.
[Abstract/Free Full Text] - Zhu XY, Daghini E, Chade AR, Rodriguez-Porcel M, Napoli C, Lerman A, Lerman LO. Role of oxidative stress in remodeling of the myocardial microcirculation in hypertension. Arterioscler Thromb Vasc Biol. 2006; 26: 1746–1752.
[Abstract/Free Full Text] - Zhu XY, Chade AR, Rodriguez-Porcel M, Bentley MD, Ritman EL, Lerman A, Lerman LO. Cortical microvascular remodeling in the stenotic kidney: role of increased oxidative stress. Arterioscler Thromb Vasc Biol. 2004; 24: 1854–1859.
[Abstract/Free Full Text] - Faraci FM, Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol. 2004; 24: 1367–1373.
[Abstract/Free Full Text] - Zhu XY, Daghini E, Rodriguez-Porcel M, Chade AR, Napoli C, Lerman A, Lerman LO. Redox-sensitive myocardial remodeling and dysfunction in swine diet-induced experimental hypercholesterolemia. Atherosclerosis. 2007; 193: 62–69.[CrossRef][Medline] [Order article via Infotrieve]
- Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev. 1995; 9: 794–807.
[Abstract/Free Full Text] - Zhu XY, Rodriguez-Porcel M, Bentley MD, Chade AR, Sica V, Napoli C, Caplice N, Ritman EL, Lerman A, Lerman LO. Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia. Circulation. 2004; 109: 2109–2115.
[Abstract/Free Full Text] - Crook ED, Thallapureddy A, Migdal S, Flack JM, Greene EL, Salahudeen A, Tucker JK, Taylor HA Jr. Lipid abnormalities and renal disease: is dyslipidemia a predictor of progression of renal disease? Am J Med Sci. 2003; 325: 340–348.[Medline] [Order article via Infotrieve]
- Segerer S, Nelson PJ, Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol. 2000; 11: 152–176.
[Abstract/Free Full Text] - Stabile E, Burnett MS, Watkins C, Kinnaird T, Bachis A, la Sala A, Miller JM, Shou M, Epstein SE, Fuchs S. Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice. Circulation. 2003; 108: 205–210.
[Abstract/Free Full Text] - Tamilarasan KP, Kolluru GK, Rajaram M, Indhumathy M, Saranya R, Chatterjee S. Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells. BMC Cell Biol. 2006; 7: 17.[CrossRef][Medline] [Order article via Infotrieve]
- Komorowski J, Jerczynska H, Siejka A, Baranska P, Lawnicka H, Pawlowska Z, Stepien H. Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells. Life Sci. 2006; 78: 2558–2563.[CrossRef][Medline] [Order article via Infotrieve]
- Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV. Integrin signaling is critical for pathological angiogenesis. J Exp Med. 2006; 203: 2495–2507.
[Abstract/Free Full Text] - Bruick RK, McKnight SL. Building better vasculature. Genes Dev. 2001; 15: 2497–2502.
[Free Full Text] - Donnahoo KK, Meldrum DR, Shenkar R, Chung CS, Abraham E, Harken AH. Early renal ischemia, with or without reperfusion, activates NFkappaB and increases TNF-alpha bioactivity in the kidney. J Urol. 2000; 163: 1328–1332.[CrossRef][Medline] [Order article via Infotrieve]
- Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connell JM. Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin Sci (Lond). 2000; 98: 531–535.[Medline] [Order article via Infotrieve]
- Yoshizumi M, Perrella MA, Burnett JC Jr, Lee ME. Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res. 1993; 73: 205–209.[Abstract]
- Zhao RZ, Chen X, Yao Q, Chen C. TNF-alpha induces interleukin-8 and endothelin-1 expression in human endothelial cells with different redox pathways. Biochem Biophys Res Commun. 2005; 327: 985–992.[CrossRef][Medline] [Order article via Infotrieve]
- Klemm P, Warner TD, Hohlfeld T, Corder R, Vane JR. Endothelin 1 mediates ex vivo coronary vasoconstriction caused by exogenous and endogenous cytokines. Proc Natl Acad Sci U S A. 1995; 92: 2691–2695.
[Abstract/Free Full Text] - Landray MJ, Wheeler DC, Lip GY, Newman DJ, Blann AD, McGlynn FJ, Ball S, Townend JN, Baigent C. Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study. Am J Kidney Dis. 2004; 43: 244–253.[CrossRef][Medline] [Order article via Infotrieve]
- Ren Y, Carretero OA, Garvin JL. Mechanism by which superoxide potentiates tubuloglomerular feedback. Hypertension. 2002; 39: 624–628.
[Abstract/Free Full Text] - Izzedine H, Launay-Vacher V, Deray G. Thalidomide for the nephrologist. Nephrol Dial Transplant. 2005; 20: 2011–2012.
[Free Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||