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

Nowak, Grażyna

doi:10.1124/jpet.103.050336

Cited by 25 publications

(18 citation statements)

References 39 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%

“…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]. Other studies in primary cultures of rPT cells, which enable assessment of longer term exposures at lower concentrations as compared to studies that can be conducted in suspensions of freshly isolated cells, showed that DCVC primarily caused necrosis at relatively high concentrations but that concentrations as low as 10 μM increased expression of vimentin [26].…”

Section: Introductionmentioning

confidence: 99%

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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: 99%

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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“…In contrast to plentiful data supporting the role of PKC-ε in the myocardium and cancer cells, information about the role of PKC-ε in kidney functions is very limited. Previously, we have demonstrated that PKC isoforms PKC-␣ and PKC-ε mediate nephrotoxicant-induced mitochondrial dysfunction, decreases in active transport, and injury in renal proximal tubular cells (RPTC) (29,(31)(32)(33). Oxidant-induced activation of PKC-ε in RPTC is involved in the decreases in mitochondrial function, Na ϩ -K ϩ -ATPase activity and active Na ϩ transport following oxidant injury.…”

mentioning

confidence: 99%

Protein kinase C-ε activation induces mitochondrial dysfunction and fragmentation in renal proximal tubules

Nowak

Bakajsova

Samarel

2011

American Journal of Physiology-Renal Physiology

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PKC-ε activation mediates protection from ischemia-reperfusion injury in the myocardium. Mitochondria are a subcellular target of these protective mechanisms of PKC-ε. Previously, we have shown that PKC-ε activation is involved in mitochondrial dysfunction in oxidant-injured renal proximal tubular cells (RPTC; Nowak G, Bakajsova D, Clifton GL Am J Physiol Renal Physiol 286: F307–F316, 2004). The goal of this study was to examine the role of PKC-ε activation in mitochondrial dysfunction and to identify mitochondrial targets of PKC-ε in RPTC. The constitutively active and inactive mutants of PKC-ε were overexpressed in primary cultures of RPTC using the adenoviral technique. Increases in active PKC-ε levels were accompanied by PKC-ε translocation to mitochondria. Sustained PKC-ε activation resulted in decreases in state 3 respiration, electron transport rate, ATP production, ATP content, and activities of complexes I and IV and F0F1-ATPase. Furthermore, PKC-ε activation increased mitochondrial membrane potential and oxidant production and induced mitochondrial fragmentation and RPTC death. Accumulation of the dynamin-related protein in mitochondria preceded mitochondrial fragmentation. Antioxidants blocked PKC-ε-induced increases in the oxidant production but did not prevent mitochondrial fragmentation and cell death. The inactive PKC-ε mutant had no effect on mitochondrial functions, morphology, oxidant production, and RPTC viability. We conclude that active PKC-ε targets complexes I and IV and F0F1-ATPase in RPTC. PKC-ε activation mediates mitochondrial dysfunction, hyperpolarization, and fragmentation. It also induces oxidant generation and cell death, but oxidative stress is not the mechanism of RPTC death. These results show that in contrast to protective effects of PKC-ε activation in cardiomyocytes, sustained PKC-ε activation is detrimental to mitochondrial function and viability in RPTC.

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

Cited by 25 publications

References 39 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-ε activation induces mitochondrial dysfunction and fragmentation in renal proximal tubules

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