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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
SPECIFIC AIMS
The presence of renovascular disease is an independent predictor of cardiovascular disease and cardiac events. The hallmark of renovascular disease is the development of intrarenal microvascular (IMV) injury. Renal artery stenosis (RAS), the main cause of renovascular hypertension and ischemic nephropathy, induces IMV and tissue remodeling that may lead to irreversible injury and progressive deterioration of renal function, and subsequently end-stage renal disease. Studies have shown that interventions that increase microvascular density can preserve ischemic tissues. 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 unrelated to cholesterol reduction. Statins have been shown to be renoprotective in models of renal disease, such as early atherosclerosis, acute ischemic renal failure, and ischemia/reperfusion injury, but their potential beneficial effects on the chronically ischemic kidney are unknown. Therefore, we tested 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.
PRINCIPAL FINDINGS
1. Simvastatin supplementation promotes renal neovascularization in vivo in RAS
We have recently shown that the kidney exposed to chronic RAS shows a significant attenuation in IMV density, 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. Possibly, abundance of reactive oxygen species may destabilize and accelerate degradation of the HIF-1 protein in the RAS kidney. Furthermore, slowly evolving or chronic reduction of blood flow, as occurs in RAS, may fail to increase VEGF production. Indeed, we found decreased renal protein expression of both total and P-Akt (upstream mediators of both HIF-1 and VEGF), which possibly led to the decreased HIF-1 expression and consequently VEGF protein concentration in the RAS kidney. Hence, despite evidence for the presence of some neovessels in the ischemic kidney (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 investigated the effects of simvastatin supplementation on the ischemic kidney. For this purpose, 20 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. RAS animals were divided at baseline in untreated (RAS, n =7) or chronically supplemented with simvastatin (RAS+simvastatin, 40–80 mg/day, adjusted by body wt, n =6) and studied after 12 wk, both in vivo and in vitro. Additional animals were used as controls (normal, n =7). Simvastatin supplementation restored renal expression of both HIF-1 and VEGF in the ischemic kidney, accompanied by normalized IMV density and increased abundance of angiogenic vessels (Fig. 1
), as detected by micro-computed tomography (CT) analysis and integrin + stained vessels. Interestingly, restoration of the angiogenic activity in RAS + simvastatin was reflected not only in the IMV but also by arteriogenesis of functional collaterals around the stenosis. Arteriogenesis carries a significant potential to increase blood and oxygen supply to the ischemic kidney and therefore restore renal function and size. Nevertheless, blood pressure remained elevated during simvastatin supplementation; therefore, this mechanism likely did not suffice to restore renal perfusion pressure.
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2. Simvastatin restores renal hemodynamics and function of the ischemic kidney
Single-kidney hemodynamics and function were evaluated in vivo using electron-beam CT. Notably, the improved IMV density in RAS + simvastatin animals was attended by increased renal blood flow (normal 593.6 ±65.3, RAS+simvastatin, 496.3 ±33.1, and RAS 336.6 ±99.3 ml/min, P <0.05 RAS vs. Normal) and glomerular filtration rate (normal 69.1 ±3.3, RAS+simvastatin 81.0 ±9.0, and RAS 47.9 ±10.2 ml/min, P <0.05 RAS vs. Normal), both at baseline and in response to the endothelium-dependent vasodilator acetylcholine (compared with baseline: P <0.05 for normal and RAS+simvastatin, P =NS for RAS), suggesting restoration of renal endothelial function in the ischemic kidney.
3. Simvastatin prevents IMV and tissue remodeling in RAS
Structural alterations in the microcirculation, such as inward remodeling, are considered an important mechanism of organ damage, greatly influence the progression of important vascular diseases, and may interfere with therapeutic interventions. We have shown previously that RAS was associated with increased IMV media-to-lumen ratio, decreased IMV diameter, and renal fibrosis (e.g., glomerulosclerosis, tubulo-interstitial damage). Remarkably, we observed that simvastatin also preserved the IMV bed and the structure of the ischemic kidney. Indeed, the current study demonstrated that glomerulosclerosis was increased in RAS (5.1 ±0.9%), but attenuated in RAS + simvastatin (2.1 ±1.9%, P <0.05 vs. RAS). Renal sections stained with trichrome showed increased IMV media-to-lumen ratio (0.55 ±0.06) and perivascular fibrosis in the stenotic kidney, which were substantially attenuated in RAS + simvastatin (0.28 ±0.02, P <0.05 vs. RAS). Furthermore, this study showed increased expression of vascular -SMA in RAS (a marker of vascular injury) and also suggested a role in mediating the IMV remodeling for tissue-transglutaminase (tTG), which was highly expressed in the RAS kidney but normalized after simvastatin supplementation (Fig. 2
). This cross-linking enzyme plays a pivotal role in small artery inward remodeling associated with chronic low-flow states. Importantly, tTG can also lead to extracellular-matrix accumulation, both directly and by interacting with transforming-growth factor (TGF)-ßbeta;, which was elevated in RAS and may have thereby indirectly inhibited the angiogenic response. Intrarenal buildup of fibrotic tissue may constrain and limit vascular growth in RAS and interfere with efficient angiogenesis, as might be observed during scar formation. In addition, TGF-ßbeta; may not only elicit renal fibrosis in RAS but may also modulate angiogenesis by regulation of VEGF, altering the integrin profile and further manipulating interactions of IMV endothelial cells with the extracellular-matrix during angiogenesis.
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CONCLUSIONS AND SIGNIFICANCE
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 shows that IMV rarefaction and remodeling in the ischemic kidney was substantially attenuated by simvastatin. Simvastatin supplementation decreased fibrogenic activity and increased both renal angiogenesis and arteriogenesis, and consequently renal hemodynamics and function were restored in RAS (Fig. 3
). Conceivably, dual modulation of IMV proliferation, structure, and function, as well as renal fibrosis, preserved the stenotic kidney. 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.
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FOOTNOTES
1 These authors contributed equally to this work. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-5680fje
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