Events that precede and that follow S-(1,2-dichlorovinyl)-l-cysteine-induced release of mitochondrial Ca2+ and their association with cytotoxicity to renal cells

Vamvakas, Spyridon; Bittner, Detlef; Dekant, W.; Anders, M.W.

doi:10.1016/0006-2952(92)90377-u

Cited by 40 publications

(27 citation statements)

References 36 publications

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“…Figure 6). As found previously in hPT cells [32][33][34], rPT cells [9,[12][13][14][15][17][18][19][20]26,31], and rabbit proximal tubules [21][22][23][24][25], hPT cells in the current study exhibited decreases in respiration. Modest effects were observed at 10 μM DCVC and none were detected at 1 or 5 μM DCVC.…”

Section: Discussionsupporting

confidence: 86%

“…Similar studies in isolated mitochondria from rat kidneys showed DCVC to be a potent inhibitor of respiration and several dehydrogenases [11][12][13][14][15][16][17]. Changes in mitochondrial Ca 2+ ion homeostasis also appear to be a key step in DCVC-induced renal toxicity [13,[18][19][20]. The importance of mitochondria in DCVC-induced renal toxicity is further highlighted by findings that preservation of mitochondrial function is associated with recovery and repair of epithelial cells from rabbit proximal tubules after sublethal injury from DCVC [21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 92%

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Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Papanayotou

Putt

et al. 2008

Biochemical Pharmacology

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The nephrotoxic metabolite of the environmental contaminant trichloroethylene, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is known to elicit cytotoxicity in rat and human proximal tubular (rPT and hPT, respectively) cells that involves inhibition of mitochondrial function. DCVC produces a range of cytotoxic and compensatory responses in hPT cells, depending on dose and exposure time, including necrosis, apoptosis, repair, and enhanced cell proliferation. The present study tested the hypothesis that induction of mitochondrial dysfunction is an obligatory step in the cytotoxicity caused by DCVC in primary cultures of hPT cells. DCVC-induced necrosis was primarily a highconcentration (≥ 50 μM) and lat (≥ 24 hr) response whereas apoptosis and increased proliferation occurred at relatively low concentrations (< 50 μM) and early time points (≤ 24 hr). Decreases in cellular DNA content, indicative of cell loss, were observed at DCVC concentrations as low as 1 μM. Involvement of mitochondrial dysfunction in DCVC-induced cytotoxicity was supported by showing that DCVC caused modest depletion of cellular ATP, inhibition of respiration, and activation of caspase-3/7. Cyclosporin A protected cells against DCVC-induced apoptosis and both cyclosporin A and ruthenium red protected cells against DCVC-induced loss of mitochondrial membrane potential. DCVC caused little or no activation of caspase-8 and did not significantly induce expression of Fas receptor, consistent with apoptosis occurring only by the mitochondrial pathway. These results support the conclusion that mitochondrial dysfunction is an early and obligatory step in DCVC-induced cytotoxicity in hPT cells.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 92%

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Papanayotou

Putt

et al. 2008

Biochemical Pharmacology

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“…Studies using freshly isolated rat proximal tubular cells have indicated that DCVC is a potent cytotoxin, leading to primary mitochondrial dysfunction (Lash et al, 1986a) and inhibition of mitochondrial Ca 2+ sequestration (Vamvakas et al, 1992). The importance of mitochondria in DCVC-induced nephrotoxicity is further highlighted by the studies of rabbit proximal tubules which have demonstrated that the preservation of mitochondrial function is associated with recovery and repair in damaged epithelial cells (Liu et al, 2004;Nowak et al, 1999;Nowak, 2003;Shaik et al, 2007Shaik et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

Nephrotoxic effect of subchronic exposure to <i>S</i>-(1,2-dichlorovinyl)-<i>L</i>-cysteine in mice

et al. 2012

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-The effect of subchronic exposure of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), an active metabolite of trichloroethylene (TCE), was investigated in mice, as a part of mechanistic assessment of renal toxicity of TCE. To examine the subchronic effects of DCVC on kidney function, Balb/c male mice were administered DCVC orally and intraperitoneally once a week for 13 weeks at 1, 10 and 30 mg/kg (Main Study) and for 8 weeks at 30 mg/kg (PCR Study). At the terminal sacrifice, mice orally and intraperitoneally administered with 10 and 30 mg/kg showed significantly lower kidney weight and significantly higher blood urea nitrogen levels than the control group. Pathological examination revealed that a dose of 30 mg/kg delivered by both routes resulted in renal tubular degeneration characterized by tubular necrosis and interstitial fibrosis, and in degradation of the cortex. Degenerative changes were accompanied by the increased expression of tumor necrosis factor-α, interleukin-6 and cyclooxygenase-2 mRNAs in the kidney of mice treated with 30 mg/kg for 8 weeks. These pathohistological observations mostly corresponded to those in short-term toxicity studies on DCVC. DCVC might be a direct cause of renal toxicity, which is suggested from the aggravation in these symptoms with the dose increase.

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“…Halogenated hydrocarbons represent a large group of environmental chemicals that are used as chemical intermediates, solvents, and pesticides and produce toxicity and acute renal failure (ARF) after their enzymatic conversion to reactive intermediates and the formation of nephrotoxic cysteine S-conjugates (Elfarra et al, 1986;Lash and Anders, 1987). S-(1,2-Dichlorovinyl)-L-cysteine (DCVC) is a model halocarbon nephrotoxicant that is selective for RPTCs and produces injury through multiple mechanisms, including mitochondrial dysfunction (Stevens et al, 1986;Lash and Anders, 1987;Vamvakas et al, 1992;van de Water et al, 1994;Anders, 1995;Chen et al, 2001).…”

mentioning

confidence: 99%

Protein Kinase C Mediates Repair of Mitochondrial and Transport Functions after Toxicant-Induced Injury in Renal Cells

Nowak

2003

J Pharmacol Exp Ther

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Previously, we have shown that renal proximal tubular cells (RPTCs) recover physiological functions after injury induced by the oxidant tert-butylhydroperoxide (TBHP), but not by the nephrotoxic cysteine conjugate dichlorovinyl-L-cysteine (DCVC). This study examined the role of protein kinase C (PKC) in the repair of RPTC functions after sublethal injury produced by these toxicants. Total PKC activity decreased 65 and 86% after TBHP and DCVC exposures, respectively, and recovered in TBHP-injured but not in DCVC-injured RPTCs. Mitochondrial function, active Na ϩ transport, and Na ϩ -dependent glucose uptake decreased after toxicant exposure and recovered in TBHP-but not in DCVC-injured RPTCs. PKC inhibition decreased the repair of RPTC functions after TBHP injury. PKC activation promoted recovery of mitochondrial function and active Na ϩ transport in TBHP-and DCVC-injured RPTCs but had no effect on recovery of Na ϩ -dependent glucose uptake. We conclude that in RPTCs, 1) total PKC activity decreases after TBHP and DCVC injury and recovers after TBHP but not after DCVC exposure, 2) recovery of PKC activity precedes the return of physiological functions after oxidant injury, 3) PKC inhibition decreases recovery of physiological functions, and 4) PKC activation promotes recovery of mitochondrial function and active Na ϩ transport but not Na ϩ -dependent glucose uptake. These results suggest that the repair of renal functions is mediated through PKC-dependent mechanisms and that cysteine conjugates may inhibit renal repair, in part, through inhibition of PKC signaling.Numerous toxicants can cause renal dysfunction through their ability to induce sublethal injury to renal proximal tubular cells (RPTCs), which results in decreased normal cellular functions without producing cell death and loss. Mitochondrial dysfunction followed by ATP depletion, reduced metabolic functions, and decreases in Na ϩ -K ϩ -ATPase activity and active Na ϩ transport are the major alterations in RPTCs injured by different toxicants (Elfara et al

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Events that precede and that follow S-(1,2-dichlorovinyl)-l-cysteine-induced release of mitochondrial Ca2+ and their association with cytotoxicity to renal cells

Cited by 40 publications

References 36 publications

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells

Nephrotoxic effect of subchronic exposure to <i>S</i>-(1,2-dichlorovinyl)-<i>L</i>-cysteine in mice

Protein Kinase C Mediates Repair of Mitochondrial and Transport Functions after Toxicant-Induced Injury in Renal Cells

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