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Article: Interstitial fibrosis in hypercholesterolemic rats: Role of oxidation, matrix synthesis, and proteolytic cascades

TitleInterstitial fibrosis in hypercholesterolemic rats: Role of oxidation, matrix synthesis, and proteolytic cascades
Authors
KeywordsRenal fibrosis
Tissue inhibitor of metalloproteinases
Urokinase-type plasminogen activator
Oxidized low-density lipoproteins
Antioxidants
Issue Date1998
Citation
Kidney International, 1998, v. 53, n. 5, p. 1182-1189 How to Cite?
AbstractUninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TGF-β1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase- type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-β1 mRNA levels (to 150%), although TGF-β1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.
Persistent Identifierhttp://hdl.handle.net/10722/205690
ISSN
2015 Impact Factor: 7.683
2015 SCImago Journal Rankings: 3.181
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorEddy, Allison Alan-
dc.contributor.authorLiu, Elaine-
dc.contributor.authorMcCulloch, Lori-
dc.date.accessioned2014-10-06T08:02:12Z-
dc.date.available2014-10-06T08:02:12Z-
dc.date.issued1998-
dc.identifier.citationKidney International, 1998, v. 53, n. 5, p. 1182-1189-
dc.identifier.issn0085-2538-
dc.identifier.urihttp://hdl.handle.net/10722/205690-
dc.description.abstractUninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TGF-β1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase- type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-β1 mRNA levels (to 150%), although TGF-β1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.-
dc.languageeng-
dc.relation.ispartofKidney International-
dc.subjectRenal fibrosis-
dc.subjectTissue inhibitor of metalloproteinases-
dc.subjectUrokinase-type plasminogen activator-
dc.subjectOxidized low-density lipoproteins-
dc.subjectAntioxidants-
dc.titleInterstitial fibrosis in hypercholesterolemic rats: Role of oxidation, matrix synthesis, and proteolytic cascades-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1046/j.1523-1755.1998.00889.x-
dc.identifier.pmid9573532-
dc.identifier.scopuseid_2-s2.0-0031869430-
dc.identifier.volume53-
dc.identifier.issue5-
dc.identifier.spage1182-
dc.identifier.epage1189-
dc.identifier.isiWOS:000073168500009-

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