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,
,2
Department of Internal Medicine,
* Divisions of Nephrology and Hypertension and
Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA;
Research Center of Excellence in Cardiovascular Diseases and Departments of General Pathology and Medicine, University of Naples, Italy; and
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University, Boston, Massachusetts, USA
2Correspondence: Division of Nephrology and Hypertension, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905, USA. E-mail: lerman.lilach{at}mayo.edu
ABSTRACT
We tested the hypothesis that statins would decrease renal injury in renal artery stenosis (RAS) by restoring angiogenesis and attenuating intrarenal microvascular (IMV) remodeling. Single-kidney hemodynamics and function were quantified using electron-beam-computed tomography (CT) in normocholesterolemic pigs after 12 wk of experimental RAS, RAS supplemented with simvastatin (RAS+simvastatin), and normal controls. Renal circulation was also studied in vivo using angiography and ex vivo using a unique 3D micro-CT imaging technique. Angiogenic and remodeling pathways were subsequently explored in renal tissue. Blood pressure and the degree of stenosis were similarly increased in RAS groups. Simvastatin in RAS enhanced both intrarenal angiogenesis and peri-stenosis arteriogenesis and increased the expression of angiogenic growth factors and hypoxia-inducible factor-1
. Furthermore, simvastatin decreased tissue-transglutaminase expression and IMV inward remodeling, restored IMV endothelial function, decreased fibrogenic activity, and improved renal function. Chronic simvastatin supplementation promoted angiogenesis in vivo, decreased ischemia-induced IMV remodeling, and improved IMV function in the stenotic kidney, independent of lipid lowering. These novel renoprotective effects suggest a role for simvastatin in preserving the ischemic kidney in chronic RAS.—Chade, A. R., Zhu, X., Mushin, O. P., Napoli, C., Lerman, A., Lerman, L. O. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia.
Key Words: kidney • ischemia • simvastatin • angiogenesis • microvessels • remodeling.
RENAL ARTERY STENOSIS (RAS), the major cause of renovascular hypertension, may induce renal tissue injury and lead to end-stage renal disease (ESRD) (1
, 2)
. Furthermore, the presence of renovascular disease is an independent predictor of cardiovascular disease and cardiac events (3)
. Notably, renovascular disease is characterized by intrarenal microvascular (IMV) disease that aggravates the effects of the obstruction in the main renal artery on the progression of renal injury and outcomes. We have recently shown that IMV density was substantially diminished in RAS (4)
, which may conceivably be the result of either altered or insufficient angiogenesis. In support of this notion, IMV rarefaction was associated with decreased expression of hypoxia-inducible factor (HIF)-1 and vascular endothelial growth factor (VEGF), as well as with impaired renal function and structure (4)
. Studies have shown that interventions that increase microvascular density can preserve ischemic tissues (5
, 6)
. However, to date few such strategies are available for effective preservation of the stenotic kidney.
Emerging evidence has demonstrated that HMG Co-A reductase-inhibitors (statins) have antioxidant, antiinflammatory, and antifibrotic effects (7
8
9)
unrelated to cholesterol reduction. Statins have been shown to be renoprotective in models of renal disease such as early atherosclerosis (9)
, acute ischemic renal failure (10)
, and ischemia/reperfusion injury (11)
. Furthermore, in coronary artery disease (12)
and in the ischemic hind-limb model (13)
, statins can also modulate angiogenesis and restore oxygen supply. However, the potential beneficial effects of simvastatin on the stenotic kidney are yet to be investigated, partly due to the lack of sensitive methods that allow evaluation of the structure and function of the ischemic kidney.
Micro-computed tomography (CT) imaging permits assessment of the 3D pattern of IMV structure in situ, providing unique and useful means for the study of spatial distribution and connectivity of microvessels within an organ. We have demonstrated the feasibility of studying renal architecture with micro-CT in early atherosclerosis (14
, 15)
and renovascular disease (4)
. In addition, electron-beam computed tomography (EBCT) is an ultrafast scanner that we have previously shown provides accurate and noninvasive quantifications of single kidney vol, regional perfusion, renal blood flow (RBF), and glomerular filtration rate (GFR) (16
17
18
19
20
21
22)
, thereby allowing evaluation of regional renal hemodynamics and function of the intact RAS kidney in vivo distal to a stenosis. Therefore, the present study was designed to test the hypothesis that chronic supplementation with simvastatin in RAS would attenuate intrarenal vascular and structural damage by restoring angiogenesis and decreasing IMV remodeling. These renoprotective effects may consequently preserve the hemodynamics and function of the ischemic kidney.
MATERIALS AND METHODS
The Institutional Animal Care and Use Committee approved all the procedures. Twenty domestic pigs (55–65 kg) were studied after 12 wk of observation. In 13 pigs, a local-irritant coil was placed in the main renal artery at baseline, and induced gradual development of unilateral RAS, as described previously (16
, 18
19
20
21
22)
. These were then randomized into two groups that were either untreated (RAS, n = 7) or chronically treated with simvastatin (RAS + simvastatin, n = 6, 40 mg/day for 5 wk and then 80 mg/day for the remaining 7 wk). The dosing in this study (adjusted to increases in the pig’s body wt) was based on clinical practice and on our previous animal studies showing pleiotropic effects at this dose, independent of lipid-lowering (9
, 23)
. The lipoprotein profile in swine is similar to that in humans (24)
, but statins are less efficacious for decreasing lipid levels in this model (25)
, thus providing an opportunity to explore their effects independent of lipid lowering. Blood pressure measurement was continuously monitored using a telemetry system (PhysioTel, Data Sciences International, Arden Hills, MN, USA) implanted at baseline in the left femoral artery. Mean arterial pressure (MAP) was recorded at 5-min intervals and averaged for each 24-h period (18
19
20
21
22)
. The other 7 pigs were used as controls (normal, n = 7).
On the day of the in vivo studies, each animal was anesthetized with 0.5 g of intramuscular ketamine and xylazine, intubated, and mechanically ventilated with room air. Anesthesia was maintained with a mixture of ketamine (0.2 mg/kg/min) and xylazine (0.03 mg/kg/min) in normal saline, administered via an ear vein cannula (0.05 µl/kg/min). Under sterile conditions and fluoroscopic guidance, an 8F arterial catheter was advanced to the stenotic renal artery, proximal to the stenosis. Short bolus injections (4–6 µl) of low-osmolar nonionic contrast media (iopamidol, Isovue-370, Squibb Diagnostics, Princeton, NJ, USA) were used to visualize the lumen of the renal artery using a fluoroscopy system (Siemens Siremobil Compact, Siemens, Munich, Germany) and magnification that allows a field of view between 17 and 23 cm. The images were recorded and later analyzed off-line to determine the degree of stenosis. After angiography, the catheter was positioned in the superior vena cava, and in vivo EBCT flow studies were performed, as previously detailed (18
19
20
21
22)
, for assessment of basal regional-renal perfusion, RBF, GFR, and tubular function. Briefly, this involved sequential acquisition of 40 consecutive scans after a central venous injection of iopamidol (0.5 cc/kg/2 s) and were repeated during suprarenal infusion of acetylcholine (Ach) (5 µg/kg/min) and sodium-nitroprusside (SNP) (6 nM/kg/min), to test endothelium-dependent and -independent responses, respectively. Blood samples were collected from the inferior vena cava for measurement of lipid profile (Roche Laboratories, Basel, Switzerland), circulating oxidized-LDL (Mercodia, Uppsala, Sweden), and plasma renin activity (PRA, radio-immunoassay).
Following completion of all studies, the pigs were euthanized with a lethal intravenous (i.v.) dose of 100 mg/kg of sodium pentobarbital (Sleepaway®, Fort Dodge Laboratories, Inc, Fort Dodge, IA, USA). Kidneys were removed using a retroperitoneal incision and immersed in Krebs’s solution containing heparin (10 U/ml) to prevent drying. A lobe of tissue was immersed in 10% buffered formalin (Sigma, St. Louis, MO, USA), and a segmental artery perfusing the intact end of the kidney cannulated and prepared for micro-CT. Another lobe of tissue was removed from one end of the kidney and shock-frozen in liquid nitrogen and stored at –80°C, or preserved in formalin (15
, 18
19
20
21
22)
. In vitro studies were then performed to assess redox status and expression of angiogenic and fibrogenic factors in the kidney. Renal vascular oxidative stress was evaluated by the expression of the NADPH-oxidase gp91phox and p47phox subunits and by in situ production of superoxide anion detected by fluorescence microscopy using dihydroethidium (DHE), as described previously (18)
.
Renal tissue concentration of vascular-endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was measured using enzyme immunoassay (ELISA), as described previously (15)
, and their receptors Flk-1, Flt-1, and FGF-R1 using Western blot. Angiogenic activity was further assessed by the protein expression of HIF-1, Akt, and integrinß3. Tissue and IMV wall remodeling were assessed in deparaffinized 5-µm-thick midhilar cross sections representative slides from RAS kidneys using trichrome, and by protein expression of transforming-growth factor (TGF)-ß, tissue transglutaminase (tTG), and -smooth muscle actin (-SMA).
Micro-CT
A saline-filled cannula was ligated in a segmental artery perfusing the intact end of the kidney, and infusion of 0.9% saline (containing 10 U/ml heparin) was initiated at 10 ml/min (Syringe Infusion Pump 22, Harvard Apparatus, Holliston, MA, USA) under physiological perfusion pressure (100 mm Hg). After 10–15 min the saline infusion was replaced with infusion (0.8 ml/min) of an intravascular contrast agent, which was a freshly mixed radio-opaque silicone polymer, containing lead chromate (Microfil MV122, Flow Tech, Inc., Carver, MA, USA). This infusion was continued until the polymer drained freely from the segmental vein. After complete polymerization, a lobe of the polymer-filled tissue was trimmed from the kidney, placed in 10% buffered formalin, glycerinated, and encased in paraffin. The paraffin encasement served to physically stabilize the lobe for scanning and prevented air exposure during the scan. The kidney samples were scanned at 0.5° increments using a micro-CT scanner, as described previously (4
, 14
, 15
, 26)
. Following the scan, three-dimensional vol images were reconstructed, consisted of cubic voxels of 20 µm on a side, and displayed at 40 µm cubic voxels for subsequent analysis.
Protein expression and Western blottings
Immunohistochemistry
Staining was performed in 5 µm of either frozen (integrin ß3, Chemicon International, Temecula, CA, USA, 1:80) or paraffin (-SMA, Sigma, 1:50) midhilar renal cross-sections. The secondary antibody, IgG Envision Plus (Dako, Carpenteria, CA, USA), was followed by staining with the Vector NovaRED substrate kit (Vector Laboratories, Burlingame, CA, USA), following vendor’s instructions.
Western blotting
Standard blotting protocols were followed, as described previously (20)
, using specific polyclonal antibodies against gp91phox, p47phox, TGF-ß, smad 4, Flk-1 and Flt-1, bFGF-R1 (Santa Cruz Biotechnology, Inc., CA; 1:200 for all), total and phosphorylated (P-) Akt (Cell Signaling, Beverly, MA, USA, 1:1000), HIF-1, and tTG, (Novus Biologicals, Littleton, CO, 1:500 and 1:200, respectively). ß-actins (Sigma, 1:500) were used as loading controls. Protein expression was determined in each kidney, and the intensities of the protein bands (one per animal) were quantified using densitometry and averaged in each group.
Data analysis
Renal angiography
The degree of RAS was measured by quantitative renal angiography (16
, 18
19
20
21
22
, 27)
and assessed as the decrease in luminal diameter of the renal artery at the most stenotic point compared with a stenosis-free segment (16
, 27)
. The filling grade of functional collaterals was scored by two independent observers and averaged, following established methods (12
, 28)
: grade 0 = No visible filling of any collateral channels, grade 1 = Collateral filling of the vessel without any dye reaching the distal segment of that vessel, grade 2 = Partial collateral filling of the distal segment of the vessel, grade 3 = Complete collateral filling of the vessel.
EBCT analysis
Manually traced regions of interest were selected in EBCT images in the aorta, renal cortex, medulla, and papilla, and their densities sampled. Time-density curves were generated and fitted with extended gamma-variate curve-fits, and the area enclosed under each segment of the curve and its first moment calculated using the curve-fitting parameters (17)
. These were used to calculate renal regional perfusion (ml/minute/g tissue), single-kidney GFR, and RBF, using previously validated methods (16
17
18
19
20
21
22
, 27)
.
Micro-computed tomography analysis
Images were digitized for reconstruction of 3-D vol images, and analyzed with the Analyze® software package (Biomedical Imaging Resource, Mayo Clinic, Rochester, MN). For analysis of the cortex, the three-dimensional tomographic images were oriented so that the z axis was parallel to the radial vessels. Based on the number of cortical sections, the cortex was tomographically divided into 10 levels obtained at equal intervals, starting at the juxtamedullary cortex. For analysis, levels 1–3 were considered as inner third, levels 4–7 as middle third, and levels 8–10 as the outer third of the cortex (14)
. The spatial density, average diameter, and vascular vol fraction (sum of cross-sectional areas of all vessel/area of the region of interest) of cortical microvessels (diameters <500 µm) were calculated in each concentration. Tortuousity index was calculated as we have recently described (4
, 26)
. Briefly, 1–3 intracortical arterioles and their branches were tomographically "dissected" in each pig, the 3D path distance (total length) and linear distance (shortest distance between endpoints) of the main branches were calculated, and the tortuousity index calculated by dividing path distance by linear distance (4
, 26)
.
Histology
Midhilar 5 µm cross sections of each kidney (1 per animal) were examined using a computer-aided image-analysis program (MetaMorph[b]®, Meta Imaging Series 6.3.2 Downingtown, PA, USA). In each representative slide, trichrome and -SMA staining was semiautomatically quantified in 15–20 fields by the computer program, expressed as percentage of staining of total surface area, and the results from all fields averaged (15
, 18
19
20
21
22)
. The in situ production of superoxide anion (detected by DHE fluorescence microscopy) was similarly quantified in 30 µm frozen renal sections. Glomerular score (percentage of sclerotic glomeruli) was assessed by recording the number of sclerotic glomeruli out of 100 counted glomeruli (19
20
21
22)
.
For quantification of vessels expressing integrin ß3, 10 fields were randomly selected from each slide (one per animal), and stained vessels counted manually in each field and averaged. The results were expressed as number of integrin+ vessels per field.
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
MAP and the angiographic degree of stenosis were similarly and significantly greater in both RAS and RAS + simvastatin compared with normal. Notably, RAS + simvastatin showed greater collateral filling around the stenosis (Table 1
, Fig. 1
a). Renal vascular resistance was substantially increased in RAS but decreased (although not normalized) in RAS + simvastatin, while systemic PRA was similar among the groups (Table 1)
. Although LDL-cholesterol was similar among the groups, circulating ox-LDL was lower in RAS + simvastatin compared with RAS, suggesting that chronic simvastatin supplementation decreased LDL oxidation (Table 1)
.
|
|
Angiogenic factors
Renal tissue concentration of VEGF and bFGF was decreased in RAS (Table 1)
as was the expression of their receptors Flt-1 and FGF-R1, and integrinß3 (Fig. 2
). Similarly, renal protein expression of HIF-1 and both total and P-Akt (a downstream mediator of VEGF) were decreased in RAS. However, most of these alterations in protein expression of angiogenic factors were prevented in RAS + simvastatin, with the exception of Flk-1 that remained increased (Fig. 2)
.
|
IMV 3D architecture
The spatial density and average diameter of cortical IMV was significantly diminished in RAS compared to the normal kidneys (Table 2
, Fig. 3
a), most evidently in the small vessels (80–120 µm) of the outer and inner cortex. However, simvastatin supplementation normalized cortical vascular density in RAS kidneys, as detected both tomographically (Table 2
, Fig. 3a
) and histologically, because vessels positively stained for integrins were also increased in RAS+simvastatin (Table 2
, Fig. 3b
). No significant differences were found between RAS and RAS + simvastatin in vascular 3D path length, linear length, or tortuousity, which were similarly increased compared to normal animals (Table 2)
.
|
|
Renal morphology and IMV structure
Glomerulosclerosis was increased in RAS but decreased in RAS + simvastatin (Fig. 4
). Renal sections stained with trichrome showed increased IMV media-to-lumen ratio and perivascular fibrosis in the stenotic kidney (Fig. 4)
, which were accompanied by a significant increase in renal expression of TGF-ß, smad4, tTG, and -SMA (Fig. 5
), suggesting increased IMV remodeling. All these changes were substantially attenuated in RAS+simvastatin (Figs. 4
and 5)
. Restoration of growth factor expression in RAS + simvastatin was accompanied by decreased NAD(P)H-oxidase expression and superoxide abundance in IMV, suggesting a decrease in vascular oxidative stress (Fig. 6
).
|
|
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IMV and renal function
Basal renal vol, RBF, and GFR were significantly decreased in RAS but normalized in RAS + simvastatin (Table 1
, Fig. 1
b). Infusion of Ach and SNP was not associated with a persistent change in blood pressure, as we have previously shown (19)
. Microvascular perfusion, RBF, and GFR responses to Ach were similarly increased in both controls and RAS + simvastatin, but remained attenuated in RAS (Fig. 1b
). On the other hand, SNP induced a significant increase in RBF (to 667.9±57.8 ml/min, P=0.04), cortical, and medullary perfusion (to 4.9±0.4, and 3.6±0.3 ml/min/g tissue, respectively, P=0.04 for both) only in normal animals, while in RAS and RAS + simvastatin these remained unchanged.
DISCUSSION
This study demonstrates that simvastatin enhanced renal angiogenesis (of intrarenal microvessels) and arteriogenesis (of functional collaterals around stenosis), attenuated IMV remodeling, improved IMV function, and decreased expression of fibrogenic factors within the ischemic kidney. Consequently, simvastatin improved renal function and morphology. Therefore, the current study implies multiconcentration effects of simvastatin in protecting the IMV network, suggesting a potential role in preserving the ischemic kidney, independent of lipid-lowering.
Angiogenesis is a major physiological response to ischemia that involves a sequence of events resulting in development of new capillaries from preexisting vessels. This complex multistep process includes cell proliferation, migration, and differentiation of endothelial cells, remodeling of extracellular matrix (ECM), and functional maturation of the newly assembled vessels, and is regulated by numerous key factors such as the Akt, HIF-1, the VEGF family, bFGF, and their receptors. HIF-1 is considered the primary defensive mechanism against hypoxia (29)
and crucial for the adaptive response to ischemia in the kidney (30)
. It is activated by hypoxia and stabilized by Akt, activates VEGF, and leads to angiogenesis. However, slowly evolving or chronic reduction of blood flow, as occurs in our RAS model, may fail to increase VEGF production (31)
. Indeed, we found decreased renal protein expression of both total and P-Akt, which possibly led to the decreased HIF-1 expression (32)
as well as VEGF and bFGF protein concentration in the RAS kidney. Furthermore, we have previously shown a decrease in HIF-1 protein expression and suggested that it may be degraded by reactive oxygen species (4)
in the RAS kidney. Consequently, despite evidence for the presence of some neovessels (e.g., increased tortuousity), the failure to adequately up-regulate the expression of angiogenic mediators may have limited the potential for IMV neovascularization in chronic RAS. The current study supports this notion by showing that decreased vascular oxidative stress by simvastatin was associated with increased HIF-1 expression as well as IMV density.
We have previously shown that simvastatin can attenuate the excessive coronary vasa vasorum neovascularization observed in the hypercholesterolemic swine (23)
. This differential effect likely reflects the tissue- and disease-specific action of statins, which augment physiological but not pathological neovascularization (33)
. At low doses, statins have a proangiogenic effect (34)
, partly mediated through activation of the Akt pathway (35)
, and have been shown to elicit angiogenesis in mice with myocardial or hind-limb ischemia (33
, 36)
. The current study extends these observations and demonstrates for the first time that chronic supplementation with simvastatin significantly increased IMV density in the ischemic kidney. This was demonstrated by the increased tomographic IMV network, sustained IMV tortuousity (characteristic of angiogenic vessels), and by increased number of IMV positive for integrin ß3, a prominent mediator and marker of angiogenesis (37)
. Therefore, the beneficial effects of simvastatin on IMV likely resulted from increased angiogenic activity (e.g., normalized renal HIF-1, VEGF, bFGF, and integrins expression) that led to generation of functional new vessels.
Interestingly, restoration of the angiogenic activity in RAS+simvastatin was reflected not only in the intrarenal microcirculation but also by arteriogenesis of functional collaterals around the stenosis, a process that is driven by local changes in shear stress and by accumulation of mononuclear cells (38)
. Arteriogenesis carries a significant potential to increase blood and oxygen supply to the ischemic kidney and therefore restore renal function and size. Nevertheless, considering the fact that MAP remained elevated during simvastatin supplementation, this mechanism likely did not suffice to restore renal perfusion pressure. Thus, future studies will be needed to determine which mechanism (angiogenesis vs. arteriogenesis) is more effective for preserving the kidney.
The hallmark of renovascular disease is the development of IMV disease distal to the obstruction in the main renal artery and we have previously shown in a pig model that it was accompanied by impairment of renal endothelial function (4
, 19
20
21)
. Furthermore, structural alterations in the microcirculation, such as inward remodeling, are considered an important mechanism of organ damage (39)
, greatly influence the progression of important vascular diseases and may interfere with therapeutic interventions (40)
. We have previously shown that RAS was associated with increased IMV media-to-lumen ratio (19)
, decreased IMV diameter (4)
, and renal fibrosis. The current study extends these observations and showed in RAS increased expression of vascular -SMA, a marker of activated fibroblasts and vascular injury (41)
. Notably, this study also suggests a role for tTG in mediating the IMV remodeling in RAS. This cross-linking enzyme has been recently shown to play a pivotal role in small artery inward remodeling associated with chronic low-flow states (42)
. Persistent vasoconstriction leads to entrenchment of reduced diameter, which is sustained by tTG by its interaction with integrins in the organization of matrix components and vascular remodeling (42)
. Importantly, tTG not only mediates IMV remodeling but can also lead to ECM accumulation both directly and by interacting with TGF-ß (43
, 44)
, and may thereby indirectly inhibit the angiogenic response (45)
. Intrarenal buildup of fibrotic tissue may constrain and limit vascular growth in RAS (4)
and interfere with efficient angiogenesis, as might be observed during scar formation. In addition, TGF-ß may not only elicit renal fibrosis in RAS (19
, 21)
but may also modulate angiogenesis by regulation of VEGF (46)
(47)
, altering the integrin profile and further manipulating interactions of IMV endothelial cells with the ECM during angiogenesis (48)
.
Clinical evidence supports and expands the use of HMG Co-A reductase-inhibitors in patients with vascular disease, regardless of their cholesterol concentration (49)
. Unlike in humans, in our normocholesterolemic pigs, simvastatin did not affect cholesterol levels. Moreover, it is not unlikely that in humans (with longer duration of ischemia) the response to statins would be less pronounced. Nevertheless, the current study indicates that simvastatin can preserve the stenotic kidney. Lipid-lowering independent effects of statins include restoration of endothelial function (via increasing NO bioavailability), reduction in inflammation, and immunological and antithrombotic modulatory actions. Moreover, it has been recently shown that statins improve progenitor cell mobilization and homing during myocardial ischemia (36)
, underscoring their ability to improve tissue structure and function by a number of parallel mechanisms. The current study shows that chronic simvastatin supplementation in RAS restores basal RBF and GFR, and improves IMV endothelial function, although the residual impairment in response to SNP implies that the smooth muscle function of these vessels may still be abnormal. The salutary effects on the renal microcirculation of the ischemic kidney were accompanied by a decrease in ox-LDL and vascular oxidative stress, which likely had a dual effect on IMV function and remodeling. Although the increase in systemic ox-LDL has not reached statistical significance in RAS compared to normal, simvastatin may have attenuated its potential for harmful effects in the ischemic kidney (50
, 51)
. The decreased oxidative stress and circulating ox-LDL possibly also increased expression of eNOS (9)
, likely augmented NO bioavailability, and thereby contributed to the improvement in endothelial function (9)
. In addition, partly by decreasing renal expression of -SMA, tTG, and the TGF-ß pathway in the ischemic kidney simvastatin also blunted IMV inward remodeling, renal fibrosis, and glomerulosclerosis. Hence, simvastatin may have improved renal structure and IMV architecture by decreasing renal fibrosis, facilitating expansion of the IMV network, and thereby restoring renal hemodynamics and function.
In summary, the current study demonstrates, for the first time, the renoprotective effect of chronic simvastatin supplementation in a large animal model of chronic renal ischemia. Our study demonstrates that IMV rarefaction and remodeling was substantially attenuated by simvastatin in RAS. Simvastatin decreased fibrogenic activity and increased both renal angiogenesis and arteriogenesis, and consequently renal hemodynamics and function were restored. Conceivably, modulation of IMV proliferation, structure, and function, as well as renal fibrosis, all contributed to the ultimate preservation of the stenotic kidney. Therefore, this study suggests novel beneficial lipid-lowering independent effects of simvastatin on the ischemic kidney, which may help in developing preventive and management strategies for patients with ischemic renovascular disease.
ACKNOWLEDGMENTS
Supported by grant numbers DK-73608, HL-77131, and EB 000305 from the NIH, and by an unrestricted Medical School grant from Merck.
FOOTNOTES
1 Both authors contributed equally to this manuscript. 
Received for publication February 1, 2006. Accepted for publication March 20, 2006.
REFERENCES
This article has been cited by other articles:
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  A. R. Chade, J. D. Krier, O. Galili, A. Lerman, and L. O. Lerman Role of Renal Cortical Neovascularization in Experimental Hypercholesterolemia Hypertension, October 1, 2007; 50(4): 729 - 736. [Abstract] [Full Text] [PDF]
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 X.-Y. Zhu, M. D. Bentley, A. R. Chade, E. L. Ritman, A. Lerman, and L. O. Lerman Early changes in coronary artery wall structure detected by microcomputed tomography in experimental hypercholesterolemia Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1997 - H2003. [Abstract] [Full Text] [PDF]
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 F. S. Czepluch and J. Waltenberger High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine: Relevance to the human situation? J. Thorac. Cardiovasc. Surg., June 1, 2007; 133(6): 1685 - 1686. [Full Text] [PDF]
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 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]
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