Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia

Alejandro R. Chade, Oren P. Mushin, Xiangyang Zhu, Martin G Rodriguez-Porcel, Joseph Peter Grande, Stephen C Textor, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

56 Citations (Scopus)

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-β 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.

Original languageEnglish (US)
Pages (from-to)772-779
Number of pages8
JournalHypertension
Volume46
Issue number4
DOIs
StatePublished - Oct 2005

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Hypercholesterolemia
Fibrosis
Kidney
Diet
Matrix Metalloproteinases
Extracellular Matrix
X Ray Computed Tomography
Endothelins
Transforming Growth Factors
Gelatin
Dyslipidemias
Real-Time Polymerase Chain Reaction
Atherosclerosis
Oxidative Stress
Swine
Collagen
Western Blotting
Cholesterol
Inflammation
Lipids

Keywords

  • Fibrosis
  • Hypercholesterolemia
  • Kidney
  • Oxidative stress
  • Remodeling

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia. / Chade, Alejandro R.; Mushin, Oren P.; Zhu, Xiangyang; Rodriguez-Porcel, Martin G; Grande, Joseph Peter; Textor, Stephen C; Lerman, Amir; Lerman, Lilach O.

In: Hypertension, Vol. 46, No. 4, 10.2005, p. 772-779.

Research output: Contribution to journalArticle

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