Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia
- 1 October 2005
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 46 (4), 772-779
- https://doi.org/10.1161/01.hyp.0000184250.37607.da
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.Keywords
This publication has 42 references indexed in Scilit:
- Reversal of Glomerular Lesions Involves Coordinated Restructuring of Glomerular MicrovasculatureJournal of the American Society of Nephrology, 2004
- Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin InhibitionHypertension, 2004
- Antioxidant Intervention Blunts Renal Injury in Experimental Renovascular DiseaseJournal of the American Society of Nephrology, 2004
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- Oxidative modulation of NF-κB signaling by oxidized low-density lipoproteinBiochemical and Biophysical Research Communications, 2003
- Risk Factors for Progression of Atherosclerosis Measured at Multiple Sites in the Arterial TreeStroke, 2003
- Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemiaKidney International, 2003
- NF- activation in endothelial cells treated with oxidized high-density lipoproteinBiochemical and Biophysical Research Communications, 2003
- Plasma lipids and risk of developing renal dysfunction: The Atherosclerosis Risk in Communities StudyKidney International, 2000
- Transforming Growth Factor-β1 Increases the Expression of Lectin-like Oxidized Low-Density Lipoprotein Receptor-1Biochemical and Biophysical Research Communications, 2000