Disturbed Ca2+-signaling by chloroacetaldehyde: A possible cause for chronic ifosfamide nephrotoxicity

Benesic, Andreas; Schwerdt, Gerald; Mildenberger, Sigrid; Freudinger, Ruth; Gordjani, N.; Gekle, Michael

doi:10.1111/j.1523-1755.2005.00657.x

Cited by 32 publications

(35 citation statements)

References 37 publications

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“…4B). This possibility is in accord with a prior study showing that forskolin, which stimulates adenylate cyclase, negates the inhibitory action of CAA on Na + /Ca 2+ exchange in renal proximal tubule cells and suggests that the action of CAA is through interaction with cAMP-PKA signaling (36). An alternative but not exclusive possibility is that the stimulation of h-oxidation by AGM furnishes more FADH 2 , which is oxidized in C-II, thus bypassing the defective C-I.…”

Section: Discussionsupporting

confidence: 79%

“…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: 49%

“…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: 68%

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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: 79%

Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 68%

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Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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“…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. 60 Excessive NO production can be cytotoxic, the result of NO's reaction with reactive oxygen and nitrogen species, leading to peroxynitrite anion formation, protein tyrosine nitration, hydroxyl radical production 61 and mitochondrial dysfunction.…”

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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“…Cell culture studies could show impairment of several transport mechanisms by CAA in renal proximal tubule cells and a concentration-dependent necrotic rather than apoptotic cell death [15,16,17,18,19]. Recently we could provide evidence for cAMP-dependent alterations in Ca 2+ -signaling by CAA in human proximal tubule cells in primary culture [20]. CAA acts as a sulfhydryl reagent and thereby impairs the proper function of proteins necessary for the balance of proliferation and apoptosis by inhibition of caspases.…”

Section: Introductionmentioning

confidence: 99%

The Nephrotoxic Ifosfamide-Metabolite Chloroacetaldehyde Interferes with Renal Extracellular Matrix Homeostasis

Benesic

Schwerdt

Hennemeier

et al. 2014

Cell Physiol Biochem

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Background/Aims: Chronic renal proximal tubule dysfunction after therapy with the antineoplastic agent ifosfamide (IFO) is often attributed to the metabolite chloroacetaldehyde (CAA). Chronic IFO-nephropathy is reported to result in tubulointerstitial fibrosis and inflammation. Methods: To elucidate possible effects of CAA on extracellular matrix homeostasis, we investigated the action of CAA on markers of extracellular matrix (ECM) homeostasis in human proximal tubule cells (RPTEC) by use of direct ELISA for extracellular collagens and gelatin zymography. Results: An increase in type III collagen and a decrease in type IV collagen abundance in the media of RPTEC could be observed after exposure to CAA in clinically relevant concentrations. CAA increased intracellular type III and decreased intracellular type IV collagen. MMP-2 activity was decreased but MMP-9 activity unchanged. The enhanced CAA-induced collagen III formation could be attenuated by the intracellular Ca²⁺-chelator BAPTA-AM, the PKA-antagonist H-89 and by extracellular acidification. CAA-induced collagen III abundance was enhanced by db-cAMP and IBMX and by protein overload. Conclusions: CAA exerts profibrotic effects on RPTEC dependent on Ca²⁺ and cAMP/PKA-signaling. These effects are enhanced by additional protein burden and attenuated by acidification.

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Disturbed Ca2+-signaling by chloroacetaldehyde: A possible cause for chronic ifosfamide nephrotoxicity

Abstract: First, CAA inhibits the Na+/Ca2+-exchanger. Second, this effect is dependent on PKA. Third, CAA induces necrotic rather than apoptotic cell death. Finally, disturbed Ca(2+) homeostasis via Na(+)/Ca(2+) exchange contributes to the nephrotoxic action of CAA in RPTEC.

Cited by 32 publications

References 37 publications

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

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

The Nephrotoxic Ifosfamide-Metabolite Chloroacetaldehyde Interferes with Renal Extracellular Matrix Homeostasis

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