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      Effects of Probucol on Renal Function and Urinary Protein Excretion in Spontaneously Hypercholesterolemic Rats Fed a Normal or High Cholesterol Diet

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          Background/Aim: Spontaneously hypercholesterolemic (SHC) rats develop hypercholesterolemia and focal glomerular sclerosis, and have been thought to be a model of lipid-induced glomerular injury. However, recent studies suggest that the hypercholesterolemia might be due to secondary mechanisms by massive proteinuria. The purpose of the present study was to determine in SHC rats the effects of a high cholesterol diet on serum lipid profiles and renal function/histology, and to examine whether or not the model of lipid-induced renal injury could be developed in a short period of the time. The effects of probucol were also studied. Methods: SHC rats were fed a high cholesterol diet for 6 weeks (H) or with probucol (HP), while control SHC rats were fed normal rat chow (N) or with probucol (P). Lipid profile and renal function/histology were examined. Results: H and HP showed increased levels of urinary protein excretion and serum creatinine, as well as extremely high serum cholesterol levels, compared with N and P. HP tended to show reduced urinary protein excretion compared with H, but the difference was not statistically significant. H and HP presented histologically characteristic changes with numerous foam cells accumulated in the glomerular mesangial area, and showed glomerular sclerosis. Conclusion: The data demonstrate that SHC rats have an intrinsically abnormal lipid metabolism, and that probucol does not exert obviously beneficial effects on renal function or lipid-lowering action. A lipid-induced renal injury model of rats was produced in 6 weeks.

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          Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades.

           James A. Eddy (1998)
          Uninephrectomized 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 (TCF-beta 1), 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-beta 1 mRNA levels (to 150%), although TGF-beta 1 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.
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            Ubiquitous localization of leukotriene A4 hydrolase in the rat nephron

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              Puromycin aminonucleoside induces apoptosis and increases HNE in cultured glomerular epithelial cells11Portions of this work were presented at the meeting of American Society of Nephrology and International Society of Nephrology (2001), and have been published in abstract form.


                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                July 2004
                03 May 2004
                : 27
                : 2
                : 96-104
                Departments of aNephrology and Endocrinology, and bInfectious Disease, School of Medicine, University of Tokyo, Tokyo, Japan
                76621 Kidney Blood Press Res 2004;27:96–104
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 49, Pages: 9
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/76621
                Original Paper


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