Adriamycin Affects Glomerular Renal Function: Evidence for the Involvement of Oxygen Radicals

Barbey, M.-M.; Fels, Lüder; Soose, Mechthild; Poelstra, Klaas; Gwinner, Wilfried; Bakker, Winston W.; Stolte, H

doi:10.3109/10715768909087942

Cited by 31 publications

(22 citation statements)

References 13 publications

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“…A common experimental model of proteinuria in rats is ADR induced nephropathy. The mechanism of the glomerular injury in this model is closely related to the generation of reactive oxygen species (ROS) [9,10,11]. ROS-mediated heparan sulfate depolymerization was reported to be associated with the glomerular basement membrane permeability in ADR nephropathy [10].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of ADR induced nephropathy is related to the generation of reactive oxygen species (ROS). ROS, induced by anthracyline metabolism, damage nucleic acids, inactivate the respiratory chain enzymes and break cellular membranes by increased lipid peroxidation products [9,10,11]. The ensuing histological feature consists of glomerular vacuolization and sclerosis, dilatation of Bowman’s capsule and tubules and interstitial lymphocyte infiltrations [12].…”

Section: Introductionmentioning

confidence: 99%

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Hyperbaric Oxygen Treatment Augments the Efficacy of a Losartan Regime in an Experimental Nephrotic Syndrome Model

Yılmaz

Korkmaz²,

Kaya³

et al. 2006

Nephron Exp Nephrol

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Background/Aims: Proteinuria is associated with oxidant stress and inflammation. Hyperbaric oxygen (HBO) treatment has anti-inflammatory and anti-oxidant effects. The aim of the study was to investigate the benefits of HBO treatment on an experimental nephrotic syndrome model. Methods: 50 male Sprague-Dawley rats weighing 255 ± 39 g were housed. Forty rats were injected 6 mg/kg adriamycin into tail veins under anesthesia to induce nephrosis, while 10 rats were spared as sham control. After the stabilization of proteinuria at the sixth week, the rats were treated for 6 weeks by losartan (n = 10, 30 mg/kg/day), HBO (n = 10, 2.8 atmosphere absolute, 90 min/day), HBO + losartan (n = 10) and vehicle (n = 10). Protein carbonyl (PCO), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were analyzed from tissue specimens. Biochemical markers were studied from venous samples and 24-hour urine was collected for proteinuria. The surviving animals at 12 weeks (vehicle group (n = 6), HBO (n = 6), losartan (n = 8), HBO + losartan (n = 10) were sacrificed. Glomerular sclerosis, tubulointerstitial and blood vessel changes were determined by semiquantitative scoring. Results: The PCO levels increased (p < 0.001), and the GPx and SOD levels decreased (p < 0.001 for both) in the nephrotic rats. In losartan and HBO groups GPx levels increased (p = 0.001, p = 0.002 respectively), but PCO and SOD levels did not change. The combination of HBO with losartan significantly increased the GPx and SOD levels (p = 0.001 for both) and decreased PCO levels (p = 0.005). HBO but not losartan significantly reduced proteinuria (p < 0.001). The combination of HBO and losartan reduced proteinuria better than the single losartan regime (p < 0.001). The effect of the combination was also noticed on the histological examination of the kidneys. The activities, appetites, weight gains, and improvement of edema were better in the HBO combined with losartan regime. Conclusions: These results indicate that the addition of HBO therapy to a conventional regime, angiotensin receptor blockers, has significant benefits in the management of proteinuria. Future clinical studies are needed to elucidate the role of HBO and other antioxidant strategies in the treatment of proteinuria.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyperbaric Oxygen Treatment Augments the Efficacy of a Losartan Regime in an Experimental Nephrotic Syndrome Model

Yılmaz

Korkmaz²,

Kaya³

et al. 2006

Nephron Exp Nephrol

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“…Furthermore, ROS were demonstrated to be involved in experimental glomerulopathies such as Adriamycin (ADR) nephropathy (25), puromycin aminonucleoside nephrosis (26), passive Heymann nephritis (27), and anti-GBM nephritis (28). ROS have been shown to cause proteinuria (29,30) and loss of HS in the isolated perfused kidney model (29).…”

Section: Heparan Sulfate (Hs)mentioning

confidence: 99%

“…Identification of the radical(s) primarily involved in HS alteration was performed by the use of specific oxygen radical scavengers. To investigate the physiological significance of ROS on GBM HSPG expression and GBM permeability, we evaluated HS alterations in the nephrotic syndrome in rats after intravenous injection of ADR (doxorubicin, a member of the anthracyclin family), since in this model the generation of ROS has been shown (25,34). The impact of ROS on GBM HSPG and HS expression and albuminuria in this model was investigated by intervention studies with radical scavengers.…”

Section: Heparan Sulfate (Hs)mentioning

confidence: 99%

Hydroxyl Radicals Depolymerize Glomerular Heparan Sulfate in Vitro and in Experimental Nephrotic Syndrome

Raats

Bakker

Born

et al. 1997

Journal of Biological Chemistry

105

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Heparan sulfate, the polysaccharide side chain of heparan sulfate proteoglycan, is important for the permselective properties of the glomerular basement membrane. In this report, we show a role for hydroxyl radicals in heparan sulfate degradation and an enhanced glomerular basement membrane permeability. First, in enzyme-linked immunosorbent assay, exposure of coated heparan sulfate (proteoglycan) to reactive oxygen species resulted in a ؎50% decrease of binding of a monoclonal antibody against heparan sulfate, whereas binding of an antibody against the core protein remained unaltered. Second, on polyacrylamide gel electrophoresis, the molecular weight of heparan sulfate exposed to radicals was reduced which indicates depolymerization. Both in enzyme-linked immunosorbent assay and gel electrophoresis, hydroxyl radicals are instrumental for heparan sulfate degradation as shown by the addition of various radical scavengers. Third, in an experimental model for human nephrotic syndrome (Adriamycin nephropathy in rats), glomerular basement membrane staining of two recently described anti-heparan sulfate antibodies (JM403 and KJ865) was reduced by 24 and 43%. Treatment of Adriamycin-exposed rats with the hydroxyl radical scavenger dimethylthiourea both reduced albuminuria by 37% (p < 0.01) and partly prevented loss of heparan sulfate staining by 53% (JM403) and 39% (KJ865) (p < 0.03). In contrast to the heparan sulfate side chains, the core protein expression and the extent of glycanation did not change in Adriamycin nephropathy. We conclude that glomerular basement membrane heparan sulfate is susceptible to depolymerization by hydroxyl radicals leading to loss of glomerular basement membrane integrity and albuminuria.Heparan sulfate (HS) 1 is the anionic polysaccharide side chain of heparan sulfate proteoglycan (HSPG) present in basement membranes, extracellular matrix, and on the cell surface of many (if not all) cell types (1-3). Several investigators have shown that HS plays an important role in the permselective properties of the glomerular basement membrane (GBM) (4, 5). Enzymatic digestion of HS by heparitinase resulted in an increased passage of native ferritin and albumin through the GBM (6, 7). Furthermore, intravenous injection of a monoclonal antibody (mAb) directed against HS induces acute, selective proteinuria in rats (8). A reduction in GBM HS-associated anionic sites was found with cationic probes in several human and experimental proteinuric glomerulopathies (9, 10). With recently developed antibodies directed against GBM HSPG core protein and the HS side chain (11, 12), we demonstrated a decrease in HS staining in the GBM in different human proteinuric glomerulopathies, whereas the staining of the HSPG core protein remained unaltered (13). The mechanism responsible for this observation remains to be elucidated. In lupus nephritis, masking of HS by autoantibodies complexed to nucleosomes is proposed as a mechanism for the decrease in HS staining and albuminuria (14). In human and experimental diabe...

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“…The mechanism(s) by which the aminonucleoside-induced glomerular damage occurs is not clearly understood; however, a role for reactive oxygen species has been implicated as mediators of glomerular injury in several models of kidney disease [3] including aminonucleoside [4] and adriamycin [5] nephrosis. Previous reports have demonstrated that hyperlipidemia has an adverse effect on glomerular function in experimental animals [b, 7].…”

Section: Madrasmentioning

confidence: 99%

In Vivo Protective Effect of Taurine on Puromycin Aminonucleoside-Induced Nephrosis in Rats.

Venkatesan¹,

Rao²,

Arul

1994

J. Clin. Biochem. Nutr.

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Adriamycin Affects Glomerular Renal Function: Evidence for the Involvement of Oxygen Radicals

Cited by 31 publications

References 13 publications

Hyperbaric Oxygen Treatment Augments the Efficacy of a Losartan Regime in an Experimental Nephrotic Syndrome Model

Hyperbaric Oxygen Treatment Augments the Efficacy of a Losartan Regime in an Experimental Nephrotic Syndrome Model

Hydroxyl Radicals Depolymerize Glomerular Heparan Sulfate in Vitro and in Experimental Nephrotic Syndrome

In Vivo Protective Effect of Taurine on Puromycin Aminonucleoside-Induced Nephrosis in Rats.

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