Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis.
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.


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-beta, 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-kappaB 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.
Chade
Alejandro R
AR
Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, Minn 55905, USA.
Rodriguez-Porcel
Martin
M
Grande
Joseph P
JP
Zhu
Xiangyang
X
Sica
Vincenzo
V
Napoli
Claudio
C
Sawamura
Tatsuya
T
Textor
Stephen C
SC
Lerman
Amir
A
Lerman
Lilach O
LO
D000818:Animals; D001161:Arteriosclerosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000098:blood supply / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051131:Receptors, Oxidized LDL; D012078:Renal Artery Obstruction / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D012079:Renal Circulation; D013552:Swine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D020778:Matrix Metalloproteinase 2