Chloroacetaldehyde- and acrolein-induced death of human proximal tubule cells

Schwerdt, Gerald; Gordjani, N.; Benesic, Andreas; Freudinger, Ruth; Wollny, Brigitte; Kirchhoff, Antje; Gekle, Michael

doi:10.1007/s00467-005-2006-6

Cited by 42 publications

(31 citation statements)

References 46 publications

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“…6A). This mode of action may explain previous observations indicating that CAA depleted cellular reduced glutathione and ATP, disturbed Ca 2+ signaling, lipid peroxidation, and, ultimately, cell necrosis and death (8,(35)(36)(37)(38)(39). The cytotoxic effect of CAA is likely due to low or no reactivity with MESNA (Fig.…”

Section: Discussionsupporting

confidence: 63%

“…In addition to the curtailment of ATP synthesis, dysfunction of C-I may lead to elevated production of superoxide radicals, causing mitochondrial DNA mutations, lipid peroxidation, and protein denaturation (35)(36)(37)(38). The current study shows that the IFOinduced inhibition of NADH:oxidoreductase was associated with a significant elevation of [NADH], inhibition of the flux through the PDH reaction, and incorporation of acetyl-CoA (derived from pyruvate) into the TCA cycle (Figs.…”

Section: Discussionmentioning

confidence: 58%

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Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and B-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 58%

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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“…6, 7). These concentrations are well below the 150 μM acrolein needed for initiation of toxicity in human proximal tubule cells (Schwerdt et al, 2006). Furthermore, the tubule cells were serum-deprived for 24 hr before acrolein treatment (Schwerdt et al, 2006) whereas the HMEC-1 cells in our studies were not.…”

Section: Acrolein-mediatedmentioning

confidence: 78%

Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells

Szadkowski¹,

Myers²

2008

Toxicology

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Acrolein is a reactive aldehyde that is a widespread environmental pollutant and can be generated endogenously from lipid peroxidation. The thioredoxin (Trx) system in endothelial cells plays a major role in the maintenance of cellular thiol redox balance, and is critical for cell survival. Normally, cells maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. In human microvascular endothelial cells, Trx1 was more sensitive than Trx2 to oxidation by acrolein. A 30-minute exposure to 2.5 μM acrolein caused partial oxidation of Trx1 but not Trx2. The active site dithiol of Trx1 was essentially completely oxidized by 5 μM acrolein whereas 12.5 μM was required for complete oxidation of Trx2. Partial recovery of the Trx1 redox status was observed over a 4 hour acrolein-free recovery period, with increases in the reduced form and decreases in the fully oxidized form. For cells treated with 2.5 or 5 μM acrolein the recovery did not require protein synthesis, whereas protein synthesis was required for the return of reduced Trx1 in cells treated with 12.5 μM acrolein. Pretreatment of cells with N-acetylcysteine (NAC) resulted in partial protection of Trx1 from oxidation by acrolein. In cells treated with acrolein for 30 min, followed by a 14-to 16-hr acrolein-free period, small but significant cytotoxic effects were observed with 2.5 μM acrolein whereas all cells were adversely affected by ≥ 12.5 μM. NAC pretreatment significantly decreased the percentage of stressed cells subsequently exposed to 5 or 12.5 μM acrolein. Given the critical role of the thioredoxins in cell survival, the ability of acrolein to oxidize both thioredoxins should be taken into account for a thorough understanding of its cytotoxic effects.

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“…56,57 It has been reported that necrosis is the predominant form of cell death by chloroacetaldehyde in human proximal tubular cell lines. 58 Furthermore, chloroacetaldehyde caused elevations of intracellular free Ca2+ by an inhibitory action on Na+/ Ca2+ exchanger, which ultimately led to the disruption of membrane integrity. 59 Nitric oxide (NO) has an important role in modulating oxidative stress and tissue damage.…”

Section: 50mentioning

confidence: 99%

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

Helal

2016

Renal Failure

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This study was designed to investigate whether the treatment with the N-acetyl-L-cysteine prior to the administration of chemotherapy drug would prevent from nephrotoxicity and the loss of reproductive performance induced from chemotherapy treatment. Female rats were divided into five equal groups of six each: 1/control group; 2/rats i.p administered saline solution; 3/rats i.p administered holoxan (50 mg/kg b.wt); 4/rats i.p administered N-acetyl-L-cysteine (160 mg/kg b.wt); 5/rats i.p administered holoxan and N-acetyl-L-cysteine at the same doses. After medications, females rats were allowed to mate with males and the pregnant rats were sacrificed on day 18 of gestation. Premating treatment with holoxan showed reduction (p50.05) in reproductive performance. Whereas administration of N-acetyl-L-cysteine prior to treatment with holoxan and then concurrently with it modulated significantly fertility index, progesterone level, decreasing postimplantation loss, resorbed fetuses and improved fetal growth. Additionally, holoxan elevated the renal nicotinamide dinucleotide phosphate (NADPH) oxidase activity, oxidative stress, renal functions and caused histological changes in renal tissue. N-Acetyl-L-cysteine treatment reduced (p50.05) renal tissue NADPH oxidase, nitric oxide, malondialdehyde and improved super oxide dismutase (SOD) depletion, elevated levels phosphate, total protein and calcium as well as prevented renal histological damages. N-Acetyl-L-cysteine can confer protection against nitrosative and oxidative stresses in renal tissue induced by holoxan by suppressing NADPH oxidase activation, malondialdehyde, nitric oxide and restoring SOD activity which led to the reduction of reactive oxygen species production and subsequently might effectively improve the gonadal hormone disturbance and reproductive functions. ARTICLE HISTORY

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Chloroacetaldehyde- and acrolein-induced death of human proximal tubule cells

Cited by 42 publications

References 46 publications

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

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