Probucol reduces renal injury in the ExHC rat.
To investigate the potential roles of oxidized lipoproteins and glomerular macrophages in the pathogenesis of lipid-induced glomerular injury, we examined the effects of administration of probucol on the development of renal injury in ExHC rats. ExHC rats are derived from the Sprague-Dawley strain and are highly susceptible to dietary hypercholesterolemic stimuli. We reported previously that ExHC rats fed a cholesterol-supplemented diet (HCD) develop proteinuria and characteristic glomerular lesions. These lesions include marked accumulation of numerous lipid-filled foam cells, which have a surface marker that identifies them as macrophages, within mesangial regions, as well as segmental clusters of foam cells that are associated with capsular adhesions, the destruction of glomerular tufts and glomerular sclerosis. ExHC rats were maintained on an HCD or on an HCD supplemented with 5% (wt/wt) probucol for 8 weeks. Probucol reduced the extent of renal injury, as evidenced by proteinuria and segmental glomerular lesions, in ExHC rats fed an HCD, in the absence of any significant reduction in plasma cholesterol levels. Both low-density lipoprotein and beta-very-low density lipoprotein isolated from the plasma of probucol-treated rats were found to be resistant to oxidative modification by cupric ions. Both the size and the number of foam cells within glomeruli in the probucol-treated rats were significantly reduced as compared to those of foam cells in the untreated rats. Probucol might reduce renal injury in ExHC rats by limiting the oxidative modification of lipoproteins and, subsequently, by restricting the foam cell transformation of macrophages within glomeruli and by inhibiting the recruitment of macrophages into glomeruli. The results of the present study may be interpreted to indicate that local glomerular oxidative modification of lipoproteins might occur in vivo, and both oxidized lipoproteins and glomerular macrophages may play important roles in the pathogenesis of lipid-induced glomerular injury.
Department of Pediatric Nephrology, Tokyo Women's Medical College, Japan.
M
M
Hattori
K
K
Ito
H
H
Kawaguchi
Y
Y
Yamaguchi
D000818:Animals; D002784:Cholesterol / Q000008:administration & dosage / Q000009:adverse effects; D004586:Electrophoresis; D005527:Food, Fortified; D006937:Hypercholesterolemia / Q000150:complications / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D011341:Probucol / Q000097:blood / Q000494:pharmacology*; D011507:Proteinuria / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D008055:Lipids; D008074:Lipoproteins; D002784:Cholesterol; D011341:Probucol