on May 15, 2003
Published online before print May 15, 2003, doi: 10.1161/01.ATV.0000077477.40824.52
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Submitted on February 26, 2003
Accepted on April 30, 2003
Mechanisms of Renal Structural Alterations in Combined Hypercholesterolemia and Renal Artery Stenosis
Alejandro R. Chade ;
From the Departments of Internal Medicine, Divisions of Hypertension (A.R.C., X.Z., S.C.T., L.O.L.) and Cardiovascular Diseases (M.R.-P., A.L.), and of Laboratory Medicine and Pathology (J.P.G.), Mayo Clinic, Rochester, Minn; the Division of Clinical Pathology (V.S.) and the Department of Medicine (C.N.), University of Naples, Naples, Italy; and the National Cardiovascular Center Research Institute (T.S.), Fujishirodai, Suita, Osaka, Japan.
* To whom correspondence should be addressed. E-mail: Lerman.Lilach{at}mayo.edu.
Objective--Atherosclerotic renovascular disease (ARVD) aggravates renal scarring more than other causes of renal artery stenosis (RAS), but the underlying pathogenic mechanisms of this potential profibrotic effect remain unclear. We tested the hypothesis that coexistence of atherosclerosis and RAS interferes with renal tissue remodeling.
Methods and Results--Single-kidney hemodynamics and function were quantified in vivo with electron-beam computed tomography in 3 groups of pigs (n=7 each): normal pigs, pigs 12 weeks after induction of unilateral RAS (RAS group), and pigs with similar-degree RAS fed a 12-week 2% hypercholesterolemic diet (HC+RAS, simulating early ARVD). Kidneys were studied ex vivo by Western blotting and immunohistochemistry. Renal volume, renal blood flow, and glomerular filtration rate were similarly decreased in RAS and HC+RAS ischemic kidneys, accompanied by similar increased expression of profibrotic factors like transforming growth factor-
, tissue inhibitor of metalloproteinase-1, and plasminogen activator inhibitor-1. Nevertheless, HC+RAS kidneys showed increased intrarenal fibrosis compared with RAS-only kidneys. Furthermore, expression of nuclear factor-
B was increased, expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems was decreased, and apoptosis was blunted.
Conclusions--Diet-induced HC superimposed on RAS accelerates the development of fibrosis in the stenotic kidney by amplifying profibrotic mechanisms and disrupting tissue remodeling. These alterations might contribute to renal disease progression in ARVD and might account for the increased propensity for end-stage renal disease.
Key words: atherosclerosis • kidney • renal disease • fibrosis
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