Effects of probucol on renal function in rats with bilateral ureteral obstruction

Modi, Kush; Morrissey, Jerry; Shah, Sudhir V.; Schreiner, George F.; Klahr, Saulo

doi:10.1038/ki.1990.280

Cited by 62 publications

(39 citation statements)

References 24 publications

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“…ROS cause tissue injury directly, such as by cleavage of peptide bonds (10), or indirectly by initiating myeloperoxidase-H202-halide reactions ( 11), or by lipid peroxidation (LPO) which results, among other consequences, in the generation of highly reactive aldehydes which can then complex with lysine residues of proteins (10)(11)(12)(13). Since there is evidence for the involvement of ROS in experimental renal diseases (7,8,11,14,15), we have examined the contribution of LPO to the development of proteinuria in PHN.…”

Section: Introductionmentioning

confidence: 99%

Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen.

Neale¹,

Ojha²,

Exner³

et al. 1994

J. Clin. Invest.

133

103

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Passive Heymann nephritis (PHN) is a model of human membranous nephropathy that is characterized by formation of granular subepithelial immune deposits in the glomerular capillary wall which results in complement activation. This is causally related to damage of the filtration barrier and subsequent proteinuria. The local accumulation of injurious reactive oxygen species (ROS) is a major effector mechanism in PHN. ROS may induce tissue damage by initiating lipid peroxidation (LPO). In turn, this leads to adduct formation between breakdown products of LPO with structural proteins, such as formation of malondialdehyde (MDA) or 4-hydroxynonenal-lysine adducts. To examine the role of LPO in the development of proteinuria we have localized MDA and 4-hydroxynoneal-lysine adducts in glomeruli of PHN rats by immunofluoresence microscopy, using specific monoclonal antibodies. By immunogold electron microscopy, MDA adducts were localized to cytoplasmic vesicles and cell membranes of glomerular epithelial cells, to the glomerular basement membrane (GBM), and also to immune deposits. Type IV collagen was specifically identified as being modified by MDA adducts, using a variety of techniques. Collagenase pretreatment of GBM extracts indicated that the NC-1 domain of type IV collagen was a site of adduct formation. When LPO was inhibited by pretreatment of PHN rats with the antioxidant probucol, proteinuria was reduced by -85%, and glomerular immunostaining for dialdehyde adducts was markedly reduced, even though the formation of immune deposits was not affected. By contrast, lowering of the serum cholesterol levels had no influence on the development of proteinuria.These findings are consistent with the premise that ROSinduced glomerular injury in PHN involves LPO and that this results not only in damage of cell membranes but in modification of type IV collagen in the GBM as well. The close temporal correlation of the occurrence of LPO with

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Section: Introductionmentioning

confidence: 99%

Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen.

Neale¹,

Ojha²,

Exner³

et al. 1994

J. Clin. Invest.

133

103

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“…Studies from our laboratory have suggested that the glomerular physiologic and tubular effects of inhibition of nitric oxide synthase with L-NMMA is greatly influenced by previous renal denervation (43). Additional studies have suggested that this may be due to an ␣ 2 -adrenergic effect (44). Phentolamine blocks both ␣ 1 -and ␣ 2 -adrenergic activity.…”

Section: Discussionmentioning

confidence: 97%

“…Phentolamine blocks both ␣ 1 -and ␣ 2 -adrenergic activity. Probucol has also been suggested to alter the development of glomerulosclerosis in a subtotal nephrectomy model (44). Mechanisms that form the basis for this prevention of glomerulosclerosis have not been fully delineated.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Glomerular Immune Injury

Narsipur¹,

Peterson²,

Smith³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Significant glomerular vasoconstriction and production of reactive oxygen species has been known to occur with exposure to anti-glomerular basement membrane antibody (AGBM-Ab) in the rat model. Previously published studies have demonstrated that such effects can be reduced by therapy with phentolamine, an ␣-adrenergic antagonist. It was hypothesized that antioxidant pretreatment with water-soluble probucol would improve glomerular hemodynamics 60 to 90 min after the administration of AGBM-Ab. These relationships were examined with both in vivo renal micropuncture and in vitro studies in rats. Single-nephron GFR (SNGFR) decreased markedly in untreated rats after AGBM-Ab as a result of afferent and efferent arteriolar vasoconstriction with consequent reductions in nephron plasma flow (SNPF) and decreases in the glomerular ultrafiltration coefficient (LpA). Basal SNGFR was increased, and SNGFR was significantly higher after AGBM-Ab in probucol-treated versus untreated rats. This finding was due solely to higher values for SNPF and prevention of afferent arteriolar constriction. A reduction in LpA after AGBM-Ab was not prevented by probucol treatment. In vitro analyses of glomeruli revealed reduced myeloperoxidase activity in antioxidant-treated rats. Lipoxygenase activity and leukotriene products, however, were not changed by antioxidant therapy, yet vasoconstriction was prevented. H 2 O 2 generation before and after formyl-methionyl-leucyl-phenylalanine stimulation was significantly reduced before and after AGBM-Ab in glomeruli harvested from rats that were treated with the antioxidant. Antioxidant therapy in this model of AGBM-Ab injury did not prevent reductions in LpA, an index of glomerular membrane damage, but did prevent afferent arteriolar vasoconstriction. Reactive oxygen species generation was reduced by probucol. The specific mechanisms whereby antioxidant therapy ameliorates glomerular hemodynamic effects will be defined in additional studies and is likely to involve either enhanced vasodilator or diminished vasoconstrictor activity.

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“…22 Modi showed that the levels of MDA were significantly higher in rats with ureteral obstruction compared with the sham-treated group. 23 In response to ROS, anti-oxidant enzymes including catalase, SOD are thought to protect cellular function. Deficiency of these anti-oxidant enzymes could enhance ROS production and renal tubulointerstitial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction

et al. 2013

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Aims: Renal fibrosis is a common outcome of chronic kidney disease. This study was designed to examine the protective effects of resveratrol (RSV) against renal fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the potential mechanism involved. Methods: Mice were randomly divided into three groups: sham-operated, UUO, and UUO/RSV (20 mgÁkg À1 Áday À1). Histological changes were examined using periodic acid-Schiff and Masson's trichrome staining after 14 days. Superoxide dismutase (SOD), malondialdehyde (MDA), and 8-OHdG levels were determined using a commercially available kit. ICAM-1, TNF-a, and TGF-b levels were measured using real-time PCR. Fibronectin levels were measured by western blot, and the Smad3 acetylation and Sirt1 were examined by immunoprecipitation and western blot. Results: Our study showed that RSV treatment significantly attenuated renal injury including extracellular matrix deposition and tubulointerstitium damage. Renal cortical mRNA levels of ICAM-1, TNF-a, and TGF-b, protein expression of fibronectin and Smad3 acetylation were significantly upregulated in the UUO group. However, treatment with RSV significantly decreased the expression of these proteins. Furthermore, RSV also decreased the levels of reactive oxygen species (ROS) including MDA and 8-OHdG, and increased the level of SOD, which protects cells against ROS damage. Conclusion: Our findings suggest that RSV treatment inhibits oxidative stress, Smad3 acetylation, and renal interstitial fibrosis. Therefore, RSV may have potential as a therapeutic target for the treatment of chronic kidney disease.

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Effects of probucol on renal function in rats with bilateral ureteral obstruction

Cited by 62 publications

References 24 publications

Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen.

Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen.

Mechanisms of Glomerular Immune Injury

Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction

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