Published Online
on September 19, 2005

A more recent version of this article appeared on October 1, 2005

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Submitted on March 25, 2005
Revised on April 18, 2005

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

Alejandro R. Chade; Oren P. Mushin; Xiangyang Zhu; Martin Rodriguez-Porcel; Joseph P. Grande; Stephen C. Textor; Amir Lerman^*; and Lilach O. Lerman

From the Department of Internal Medicine, Divisions of Nephrology and Hypertension (A.R.C., O.P.M., X.Z., S.C.T., L.O.L.) and Cardiovascular Diseases (M.R.-P., A.L., L.O.L.), and Laboratory Medicine and Pathology (J.P.G.), Mayo Clinic College of Medicine, Rochester, Minn.

^* To whom correspondence should be addressed. E-mail: lerman.lilach{at}mayo.edu.

Abstract--Dyslipidemia often accompanies and accelerates renal disease, partly by promoting fibrosis. However, the mechanisms mediating this effect are unclear. We hypothesized that hypercholesterolemia modulates several interlinked pathways that promote deposition and blunt degradation of extracellular matrix, and that these could be manipulated by reversal of hypercholesterolemia. Fourteen pigs were fed a 16-week 2% high-cholesterol diet (HC-HC; n=7) or normal diet (n=7), whereas in 7 others, a 10-week HC was followed by a 6-week normal diet (HC-N). Renal endothelial function was assessed in vivo with electron-beam computed tomography, and renal tissue was then studied ex vivo using Western blot, real-time quantitative polymerase chain reaction, gelatin zymography, and immunostaining. HC-HC kidneys showed endothelial dysfunction, accompanied by increased intrarenal oxidative stress, inflammation, activation of the endothelin and transforming-growth factor- systems, and decreased matrix metalloproteinase expression and activity. Accordingly, HC-HC kidneys showed increased collagen IV expression and fibrosis. A lipid-lowering dietary intervention reversed most of these changes. In conclusion, this study indicates that renal fibrosis in early atherosclerosis is a result of a simultaneous increase in extracellular matrix deposition and blunted matrix metalloproteinase-mediated degradation, overall promoting perivascular and tubulointerstitial fibrosis. Notably, many of these pathways may be reversible in hypercholesterolemia, and crucial targets could potentially be identified for early interventions to preserve the kidney.

Key words: kidney • hypercholesterolemia • fibrosis • remodeling • oxidative stress

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