cytochrome-c-t and Kidney-Diseases

The mechanistic link between obesity and renal failure has been proposed to involve mitochondria reactive oxygen species generation and lipotoxicity. These pathological conditions make mitochondria of particular interest in the regulation of cell function and death by both apoptosis and autophagy. Therefore, this work was undertaken to investigate mitochondria function, autophagy, and apoptosis protein markers in the kidney from a rat model of intra-abdominal obesity and renal damage induced by a high-sucrose diet. Mitochondria from sucrose-fed (SF) kidneys in the presence of pyruvate-malate generated H

Topics: Animals; Apoptosis; Autophagy; Biomarkers; Cardiolipins; Cytochromes c; Dietary Sucrose; Hydrogen Peroxide; Kidney; Kidney Diseases; Male; Mitochondria; Rats; Rats, Wistar; Reactive Oxygen Species

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Canagliflozin; Cells, Cultured; Cisplatin; Cytochromes c; Cytoprotection; Disease Models, Animal; Enzyme Activation; JNK Mitogen-Activated Protein Kinases; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Tumor Suppressor Protein p53

Tenofovir disoproxil fumarate (TDF) is currently the only nucleotide analogue reverse-transcriptase inhibitor that is approved by the Food and Drug administration (FDA), USA, for the treatment of human immunodeficiency virus (HIV) infection. In recent days, renal toxicity is becoming common i HIV patients treated with TDF. However, the mechanism of tenofovir nephrotoxicity is not clear. We hypothesized that mitochondrial pathway of apoptosis, poly [ADP-ribose] polymerase (PARP) overactivation and neutrophil infiltration may contribute to tenofovir-induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body weight daily for five consecutive weeks. Kidneys were removed and used for histological and biochemical analyses. Apoptosis was detected by terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick end-labelling (TUNEL) assay and caspase 3 activity and protein expression; mitochondrial pathway of apoptosis by cyt c release; and PARP activation by immunofluorescence, immunohistochemistry and Western blot techniques. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil infiltration. TDF administration resulted in increased number of TUNEL-positive cells, activation of caspase 3 and release of cyt c from mitochondria into the cytosol in the kidneys. There was increased nuclear localization of PARP as well as increase in its protein level in the TDF-treated rat kidneys. In addition, renal MPO activity was increased ninefold as compared to controls. The results of the present study show that mitochondrial apoptotic pathway, PARP overactivation and neutrophil infiltration contribute to tenofovir-induced renal damage in rats.

Topics: Animals; Anti-HIV Agents; Apoptosis; Cytochromes c; Kidney; Kidney Diseases; Male; Mitochondria; Necrosis; Neutrophils; Peroxidase; Poly(ADP-ribose) Polymerases; Rats, Wistar; Tenofovir

Radiocontrast-induced nephropathy (CIN) is the third most common cause of acute renal failure. The pathophysiology of CIN is related to tubular injury caused by oxidative stress, and nuclear factor erythroid-2-related factor 2 (Nrf2) is critical in coordinating intracellular antioxidative processes. We thus investigated the role of Nrf2 in CIN. CIN was established in mice and in NRK-52E cells via iohexol administration according to the protocols of previous studies. To determine the role of Nrf2 in CIN, Nrf2 expression was reduced in vivo using Nrf2 knockout (KO) mice (B6.129 × 1-Nfe2 l2tm1Ywk/J) and in vitro with siRNA treatment targeting Nrf2. Increased Nrf2 expression was observed after iohexol treatment both in vivo and in vitro. Serum creatinine at 24 h after iohexol injection was significantly higher in KO mice than in wild-type (WT) mice. Histologic examination showed that iohexol-induced tubular vacuolization and structural disruption were aggravated in Nrf2 KO mice. Significant increases in apoptosis and F4/80(+) inflammatory cell infiltration were demonstrated in KO mice compared to WT mice. In addition, the increase in reactive oxygen species after iohexol treatment was augmented by Nrf2 inhibition both in vivo and in vitro. Nrf2 may be implicated in the pathogenesis of CIN via the modulation of antioxidant, anti-apoptotic, and anti-inflammatory processes.

Topics: Animals; Caspase 3; Cell Death; Cell Line; Cell Survival; Contrast Media; Creatinine; Cytochromes c; Gene Knockdown Techniques; Heme Oxygenase-1; Iohexol; Kidney Diseases; Kidney Tubules; Macrophages; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Rats; Reactive Oxygen Species

Contrast-induced nephropathy (CIN) is a relatively infrequent complication after percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI). However, little is known about the association between cytochrome c (cyt c) and increased risk of CIN. We conducted this study to explore the impact of serum cyt c on the occurrence of CIN.. We prospectively examined cyt c levels before undergoing PCI in 240 patients with STEMI. The logistic regression was performed to identify the independent risk factors for the occurrence of CIN. The receiver operating characteristic (ROC) analysis was employed to evaluate the predictive value of cyt c for the occurrence of CIN.. 29 patients (12.1%) had developed CIN after the PCI procedure. The cyt c levels at baseline were significantly higher in patients who developed CIN than those in non-CIN group (0.65±0.08 versus 0.58±0.1; P = 0.001). The multivariate logistic regression showed that cyt c was an independent risk factor for the occurrence of CIN (OR, 7.421; 95% CI, 6.471-20.741; P = 0.034) after adjusting for age, history of hypertension and diabetes mellitus, levels of creatinine, uric acid, and glucose. The ROC curve analysis showed that the area under the curve of cyt c was 0.697 (95% CI, 0.611-0.783; P = 0.001), and cyt c > 0.605 ng/mL predicted CIN with sensitivity of 79.3% and specificity of 56.9%.. Our results show that a higher cyt c level was significantly associated with the occurrence of CIN after PCI in STEMI patients. This study has been registered in the Chinese Clinical Trial Registry. The clinical trial registration number is ChiCTR1800019368.

Topics: Aged; Contrast Media; Creatinine; Cytochromes c; Female; Humans; Kidney Diseases; Logistic Models; Male; Middle Aged; Percutaneous Coronary Intervention; Risk Assessment; Risk Factors; ST Elevation Myocardial Infarction

The clinical use of glycopeptide antibiotic vancomycin is usually accompanied by nephrotoxicity, limiting its application and therapeutic efficiency. The aim of this study was to investigate the protection of DHA-enriched phosphatidylcholine (DHA-PC) against nephrotoxicity using a model of vancomycin-induced male BALB/c mice with renal injury by measuring death curves, histological changes, and renal function indexes. The addition of DHA in DHA and DHA-PC groups were 300 mg/kg per day on the basis of human intake level in our study. Results indicated that DHA-PC could dramatically extend the survival time of mice, while traditional DHA and PC had no significant effects. Moreover, oral administration of DHA-PC exhibited better effects on reducing vancomycin-induced increases of blood urea nitrogen, creatinine, cystatin C, and kidney injury molecule-1 levels than traditional DHA and PC. DHA-PC significantly delayed the development of vancomycin-induced renal injury, including tubular necrosis, hyaline casts, and tubular degeneration. A further mechanistic study revealed that the protective effect of DHA-PC on vancomycin-mediated toxicity might be attributed to its ability to inhibit oxidative stress and inactivate mitogen-activated protein kinase (MAPK) signaling pathways, which was associated with upregulation of Bcl-2 and downregulation of caspase-9, caspase-3, cytochrome-c, p38, and JNK. These findings suggest that DHA-PC may be acted as the dietary supplements or functional foods against vancomycin-induced nephrotoxicity.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Caspase 3; Caspase 9; Cytochromes c; Docosahexaenoic Acids; Humans; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Oxidative Stress; Phosphatidylcholines; Protective Agents; Vancomycin

To investigate the effects of Huaiqihuang Granules (, HQH), a mixture of Chinese herbs including Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, on adriamycininduced nephropathy (ADRN) in rats and its underlying mechanisms.. Rats with ADRN were divided into four groups: the sham group, the model group (distilled water), the low-dose HQH-treated (2 g/kg) group, and the high-dose HQH-treated (4 g/kg) group. Body weight and 24-h urinary protein (Upro) were checked every week. After 5-week intervention, at the end of the study, the rats were sacrificed and blood samples were collected for examination of biochemical parameters, including glomerular morphological makers, podocyte shape, cellular apoptosis, expressions of nephrin, inflammatory and apoptosis markers.. HQH ameliorated the rat's general status, proteinuria, renal morphological appearance and glomerulosclerosis. The decreased expression of nephrin in ADRN rats was increased by HQH, as well as the impaired podocyte foot process fusion. Cytosolic levels of p65 and inhibitor of nuclear factor κBα (IκBα) were decreased in ADRN rats, and recovered by the treatment of HQH. Consistently, the induced expression of tumor necrosis factor α (TNF-α), phosphorylated nuclear factor κB p65 (p-NFκB p65) and IκBα in ADRN were markedly suppressed by HQH. In addition, induction of Bax, cleaved caspase-3 and cytochrome C in ADRN rats were suppressed by HQH, indicating the amelioration of apoptosis.. HQH could ameliorate renal impairments in ADRN rats by increasing nephrin expression, inhibiting NF-κB signaling pathway via the down-regulation of p-NF-κB p65 and p-IκBα, and suppression of glomerular and tubular apoptosis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Body Weight; Caspase 3; Chromatography, High Pressure Liquid; Cytochromes c; Doxorubicin; Drugs, Chinese Herbal; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Male; Membrane Proteins; NF-kappa B; NF-KappaB Inhibitor alpha; Organ Size; Proteinuria; Rats, Sprague-Dawley; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Diallyl disulfide (DADS) is a degradation product of allicin which is contained in garlic. This study investigated the protective effects of DADS against acetaminophen (AAP)-induced nephrotoxicity and the molecular mechanisms of nephroprotective effects in rats. AAP caused severe nephrotoxicity as evidenced by significant increases in renal tubular cell apoptosis, mitochondria-mediated apoptosis, and up-regulation of nuclear transcription factor kappa-B (NF-κB), cyclooxygenase-2 (Cox-2), and tumor necrosis factor-α (TNF-α) in the kidney with histopathological alterations. After AAP administration, glutathione content and activities of catalase, superoxide dismutase, and glutathione reductase were significantly decreased whereas malondialdehyde content was significantly increased, indicating that AAP-induced kidney injury was mediated through oxidative stress. In contrast, DADS pretreatment significantly attenuated AAP-induced nephrotoxic effects, including oxidative damage, histopathological lesions, and apoptotic changes in the kidney. DADS also attenuated AAP-induced up-regulation of NF-κB, Cox-2, and TNF-α in the kidney, and microsomal CYP2E1 expression in liver and kidney. These results indicated that DADS could prevent AAP-induced nephrotoxicity. The protective effects of DADS might be due to its ability to decrease metabolic activation of AAP by inhibiting CYP2E1 and its potent antioxidant, antiapoptotic, and antiinflammatory effects via inhibition of NF-κB.

Topics: Acetaminophen; Allyl Compounds; Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cyclooxygenase 2; Cytochrome P-450 CYP2E1; Cytochromes c; Disulfides; Kidney; Kidney Diseases; Liver; Male; NF-kappa B; Protective Agents; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the possible protective effect of ellagic acid (EA) against gentamicin (GEN)-induced nephrotoxicity using biochemical, molecular and histopathological approaches.. Rats (n = 24) were divided into four groups: control, GEN (100 mg/kg, i.p.), EA (10 mg/kg, p.o.) and GEN plus EA. The regimes were administered for 10 successive days. 24 h after last treatment, kidney and blood samples were collected.. Ellagic acid treatment significantly reduced plasma creatinine and urea levels, which were initially increased due to GEN administration. Also, EA significantly ameliorated oxidative stress markers including lipid peroxidation, catalase (CAT) and superoxide dismutase (SOD) enzyme activity as well as glutathione (GSH) content in kidney tissue. Activation of caspase-3 and increase in the ratio of Bcl-2/Bax expression observed in GEN-treated group were significantly ameliorated by EA treatment. EA also protected GEN-induced mitochondrial damages as indicated by decreasing the mitochondrial ROS content, preventing of mitochondrial membrane potential (MMP) loss, reducing mitochondrial swelling and decreasing cytochrome c release. In addition, histopathological findings revealed that EA ameliorates GEN-induced kidney injury.. Our findings suggest that EA treatment attenuates GEN-induced nephrotoxicity, which may be ascribed to its antioxidant and anti-apoptotic properties.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Apoptosis; Caspase 3; Creatinine; Cytochromes c; Ellagic Acid; Gentamicins; Glutathione; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Superoxide Dismutase; Urea

Cis-diammine dichloroplatinum (CDDP) is one of the most important chemotherapeutic agents for cancer treatment. Nonetheless, its notable side effect, nephrotoxicity, undermines its clinical use. The current study was undertaken to evaluate the protective potential of the aqueous extract (AEC) of Cinnamomum cassia (cinnamon) against the cytotoxic effect of CDDP in vitro and to elaborate the molecular mechanism underlying protection.. MTT assay was performed to assess viability of the normal kidney Vero cells treated with CDDP and/or AEC. Cells were stained with Coomassie blue, acridine orange and ethidium bromide to highlight morphological features of apoptosis. Caspase-3 activity, DNA fragmentation and reactive oxygen species (ROS) level were monitored to assess biochemical hallmarks of apoptosis. Quantitative RT-PCR and Western blot analyses were performed to elucidate expression of cellular molecules underlying the protective potential of AEC.. CDDP-treated Vero cells exhibited hallmarks of apoptosis; these hallmarks were significantly suppressed in the presence of AEC. AEC did not alter activity of CDDP-induced cytotoxicity of breast and liver cancer cells. AEC treatment of Vero cells prevented CDDP-induced increased expression of mitochondrial Bax protein, release of mitochondrial cytochrome c, caspase-3 activation, DNA fragmentation and generation of ROS. AEC up-regulated expression of the cytoprotective gene (heme oxygenase (HO)-1).. These findings suggest AEC has protective effects against CDDP-induced toxicity via preventing the activation of various cellular mechanisms mediating apoptotic cell death, without compromising the anticancer efficiency of CDDP. Thus, cinnamon may represent one of the most feasible ways to reduce the risk of CDDP-induced toxicity.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Chlorocebus aethiops; Cinnamomum zeylanicum; Cisplatin; Cytochromes c; DNA Fragmentation; Kidney Diseases; Phytotherapy; Plant Bark; Plant Extracts; Reactive Oxygen Species; Up-Regulation; Vero Cells

Taxol and dichloroacetic acid (DCA) are anticancer agents with potential renal toxicity. Previously, we have shown that the Ser36-phosphorylated p66shc adaptor protein mediates renal toxicity of selected anticancer modalities through increasing production of intracellular reactive oxygen species and consequent mitochondrial depolarization. Here, we analyzed whether p66shc plays a role in potential renal toxicity of Taxol and DCA.. Cultured renal proximal tubule cells (TKPTS) were used. ROS production, mitochondrial depolarization (JC-1), cell injury [lactate dehydrogenase (LDH) release] and Ser36 phosphorylation of p66shc were determined after treatment with Taxol and DCA. Involvement of p66shc in adverse effects of these drugs was determined in p66shc knockdown, Ser36 phosphorylation (S36A) and cytochrome c-binding (W134F)- deficient cells.. Both Taxol and DCA increased ROS production, mitochondrial depolarization, injury and Ser36 phosphorylation of p66shc in TKPTS cells. We showed that ROS production is responsible for mitochondrial depolarization and consequent injury. Knockdown of p66shc, mutation of its Ser36 (S36A) or cytochrome c binding site (W134F) attenuated adverse effects of the two drugs.. Taxol and DCA are potentially nephrotoxic owing their adverse effects on activation of p66shc. Manipulation of expression or activity of p66shc may provide a means of ameliorating nephrotoxicity of these agents.

Topics: Animals; Cytochromes c; Dichloroacetic Acid; Gene Knockdown Techniques; Kidney Diseases; Kidney Tubules, Proximal; Membrane Potential, Mitochondrial; Mice; Mitochondria; Paclitaxel; Phosphorylation; Phosphoserine; Protein Binding; Reactive Oxygen Species; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1

Vascular calcification is prevalent in patients with chronic kidney disease and leads to increased cardiovascular morbidity and mortality. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. This study investigated the effect of α-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity and concurrently increased production of reactive oxygen species. These Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. Intriguingly, ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced down-regulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. Finally, ALA significantly ameliorated vitamin D(3) -induced aortic calcification and mitochondrial damage in mice. Collectively, the findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; preservation of mitochondrial function via its antioxidant potential and restoration of the Gas6/Axl/Akt survival pathway.

Topics: Animals; Apoptosis; Axl Receptor Tyrosine Kinase; Calcium; Caspase 3; Caspase 9; Cells, Cultured; Cholecalciferol; Cytochromes c; DNA Fragmentation; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mitochondria; Muscle, Smooth, Vascular; Phosphates; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Thioctic Acid; Vascular Calcification; Vascular Diseases

Tenofovir disoproxil fumerate (TDF) is an effective nucleoside reverse transcriptase inhibitor for HIV infection but it is potentially nephrotoxic. A selective mithochondrial toxicity has been hypothesized. To assess early markers of renal toxicity, we evaluated a cohort of antiretroviral (ARV)-experienced HIV patients who had been switched from a thymidinic backbone to either a TDF/emtricitabine regimen (TDF; 73 patients) or an abacavir/lamivudine (ABV) regimen (28 patients). Markers of mitochondrial toxicity (cytochrome c, Cyc) or cytosolic (α-glutathione S transferase, α-GST) together with common indicators of renal damage were assessed at baseline (T0) and after 1 (T1), 3 (T2), 6 (T3), and 12 (T4) months of patient exposure to therapy. Clinical features of both groups were comparable at T0. There was no significant variation in estimated glomerular filtration rate (eGRF), median urine protein excretion, or microalbuminuria and serum phosphate levels in both groups during the study period. There was a significant increase in urinary excretion of phosphate in patients on TDF compared to those on ABV at T3 and T4. Fractional excretion of uric acid was also altered in the two treatment groups; there was no change in the ABV (constantly less than 0.10), but a progressive increase in TDF patients. Serum potassium levels were significantly lower in ABV than in TDF treated patients. Urine concentrations of α-GST showed a nonsignificant variation in both groups, while Cyc excretion was significantly higher at T1 and T3 in TDF-treated compared to ABV-treated patients. In conclusion, TDF may be associated with subclinical mitochondrial damage, inducing at a later stage increased urinary excretion of phosphate and uric acid, as markers of incipient tubular injury.

Topics: Adenine; Anti-HIV Agents; Biomarkers; Cohort Studies; Cytochromes c; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Glomerular Filtration Rate; Glutathione Transferase; HIV Infections; Humans; Kidney Diseases; Kidney Tubules, Proximal; Lamivudine; Male; Middle Aged; Mitochondria; Organophosphonates; Tenofovir; Time Factors

Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (-)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction.

Topics: Animals; Antioxidants; Catechin; Cells, Cultured; Cisplatin; Cytochromes c; Disease Models, Animal; HeLa Cells; Humans; In Vitro Techniques; Kidney Diseases; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Reactive Oxygen Species; Succinate Dehydrogenase

Hexokinase (HK), the rate-limiting enzyme in glycolysis, controls cell survival by promoting metabolism and/or inhibiting apoptosis. Since HK isoforms I and II have mitochondrial targeting sequences, we attempted to separate the protective effects of HK on cell metabolism from those on apoptosis. We exposed renal epithelial cells to metabolic stress causing ATP depletion in the absence of glucose and found that this activated glycogen synthase kinase 3β (GSK3β) and Bax caused mitochondrial membrane injury and apoptosis. ATP depletion led to a progressive HK II dissociation from mitochondria, released mitochondrial apoptosis inducing factor and cytochrome c into the cytosol, activated caspase-3, and reduced cell survival. Compared with control, adenoviral-mediated HK I or II overexpression improved cell survival following stress, but did not prevent GSK3β or Bax activation, improve ATP content, or reduce mitochondrial fragmentation. HK I or HK II overexpression increased mitochondria-associated isoform-specific HK content, and decreased mitochondrial membrane injury and apoptosis after stress. In vivo, HK II localized exclusively to the proximal tubule. Ischemia reduced total renal HK II content and dissociated HK II from proximal tubule mitochondria. In cells overexpressing HK II, Bax and HK II did not interact before or after stress. While the mechanism by which HK antagonizes Bax-mediated apoptosis is unresolved by these studies, one possible scenario is that the two proteins compete for a common binding site on the outer mitochondrial membrane.

Topics: Adenosine Triphosphate; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Survival; Cells, Cultured; Cytochromes c; Disease Models, Animal; Epithelial Cells; Glucose; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hexokinase; Kidney Diseases; Kidney Tubules, Proximal; Mice; Mitochondrial Membranes; Opossums; Protein Transport; Reperfusion Injury; Signal Transduction; Stress, Physiological; Time Factors; Transfection

Mercuric chloride (HgCl₂) causes acute oxidant renal failure that affects mainly proximal tubules. Schisandrin B (Sch B), an active lignan from the fruit of Schisandra chinensis, has been successfully used to treat gentamicin nephrotoxicity, but its role against mercury damage is still largely unknown. Here we analysed in vivo and in vitro the efficacy of Sch B supplementation against HgCl₂ nephrotoxicity, focusing on histopathology, stress proteins, oxidative (cytochrome c oxidase) and nitrosactive markers (eNOS, nNOS). Wistar rats were treated with Sch B (10 mg/kg/day p.o.) or vehicle (olive oil) for 9 days, then coadministered with a single HgCl₂ nephrotoxic dose (3.5 mg/kg i.p.) and killed after 24 h. The tubular and mitochondrial damage induced by mercury was limited by Sch B coadministration in vivo. Remarkably, after Sch B and mercury challenge, HSP25, HSP72, GRP75 were reduced in the renal cortex, cytochrome c oxidase increased and eNOS and nNOS were restored in glomeruli. In contrast, NRK-52E proximal tubular cells treated with Sch B 6.25 μM plus HgCl₂ 20 μM did not show any amelioration on viability and oxidative stress in respect to HgCl₂ 20 μM alone. Moreover, after Sch B plus mercury in vitro treatment, HSP72 staining persisted while HSP25 further increased. Thus, in our experimental conditions, Sch B cotreatment afforded better protection against mercury poisoning in vivo than in vitro. This discrepancy might be partly attributable to Sch B influence on glomerular perfusion as corroborated by the recovery of vasoactive markers like macular and endothelial nitric oxide isoforms.

Topics: Animals; Cell Line; Cyclooctanes; Cytochromes c; Dose-Response Relationship, Drug; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Kidney Cortex; Kidney Diseases; Kidney Tubules, Proximal; Lignans; Male; Membrane Proteins; Mercuric Chloride; Mitochondria; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Oxidative Stress; Polycyclic Compounds; Rats; Rats, Wistar

Tubulo-interstitial nephritis antigen (TINag) is an extracellular matrix protein expressed in tubular basement membranes. Combined mutations in TINag and nephrocystin-1 genes lead to nephronophthisis with reduced cell survival. Because certain extracellular matrix proteins are known to modulate cell survival, studies were initiated in Lewis rats lacking TINag to assess if they are more susceptible to cisplatin-induced injury. Cisplatin induced a higher degree of tubular cell damage and apoptosis in regions where TINag is expressed in a parental Wistar strain. This was accompanied by an accentuated increase in serum creatinine and Kim-1 RNA and renal expression of Bax, p53, and its nuclear accumulation, mtDNA fragmentation, and a decrease of Bcl-2. Cisplatin induced fulminant apoptosis of HK-2 cells with increased caspase3/7 activity, mtDNA fragmentation, and a reduced cell survival. These effects were partially reversed in cells maintained on TINag substratum. Far Western/solid phase assays established TINag binding with integrin αvβ3 comparable with vitronectin. Transfection of cells with αv-siRNA accentuated cisplatin-induced apoptosis, aberrant translocation of cytochrome c and Bax, and reduced cell survival. The αv-siRNA decreased expression of integrin-recruited focal adhesion kinase (FAK) and p-FAK, while increasing the expression of p53 and p-p53. Similarly, p-AKT was reduced although ILK was unaffected. Inhibition of PI3K had similar adverse cellular effects. These effects were ameliorated in cells on TINag substratum. In vivo, a higher degree of decrease in the expression of p-FAK and pAKT was observed in Lewis rats following cisplatin treatment. These in vivo and in vitro studies demonstrate an essential role of TINag in cellular survival to maintain proper tubular homeostasis utilizing integrin αvβ3 and downstream effectors.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 7; Cell Line; Cell Survival; Cisplatin; Cytochromes c; Extracellular Matrix; Extracellular Matrix Proteins; Focal Adhesion Kinase 1; Gene Expression Regulation; Glomerular Basement Membrane; Integrin alphaVbeta3; Kidney Diseases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Lew; Rats, Wistar; Signal Transduction; Species Specificity; Tumor Suppressor Protein p53

The antidiabetic drug metformin can diminish apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction even in nondiabetic patients. Here we tested whether it has a beneficial effect in a rat model of gentamicin toxicity. Mitochondrial analysis, respiration intensity, levels of reactive oxygen species, permeability transition, and cytochrome c release were assessed 3 and 6 days after gentamicin administration. Metformin treatment fully blocked gentamicin-mediated acute renal failure. This was accompanied by a lower activity of N-acetyl-beta-D-glucosaminidase, together with a decrease of lipid peroxidation and increase of antioxidant systems. Metformin also protected the kidney from histological damage 6 days after gentamicin administration. These in vivo markers of kidney dysfunction and their correction by metformin were complemented by in vitro studies of mitochondrial function. We found that gentamicin treatment depleted respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. These injuries, partly mediated by a rise in reactive oxygen species from the electron transfer chain, were significantly decreased by metformin. Thus, our study suggests that pleiotropic effects of metformin can lessen gentamicin nephrotoxicity and improve mitochondrial homeostasis.

Topics: Acetylglucosaminidase; Animals; Antioxidants; Apoptosis; Cytochrome c Group; Cytochromes c; Electron Transport; Gentamicins; Hypoglycemic Agents; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Metformin; Mitochondria; Oxidation-Reduction; Oxidative Stress; Permeability; Rats; Reactive Oxygen Species

The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Caspase 3; Cisplatin; Coloring Agents; Cytochromes c; Cytoskeleton; Immunohistochemistry; Kidney Diseases; Male; Mitochondria; Molsidomine; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Peroxynitrous Acid; Phalloidine; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Renal injury is a severe and extremely common complication that occurs early in neonates with asphyxia. Reperfusion injury has been suggested as the cause of kidney damage during resuscitation of neonatal asphyxia. Previous studies have demonstrated that postasphyxial serum from neonates with asphyxia may result in apoptosis of renal tubular cells. However, the mechanisms that mediate renal tubular cell apoptosis induced by postasphyxial serum remain poorly understood.. In this report we investigate the intracellular signal transduction mechanisms that operate during injury of renal tubular cells induced by postasphyxial serum in neonates.. Cultured human renal proximal tubular cells HK-2 cell were exposed to 10% fetal calf serum (normal control), 20% postasphyxial serum or 20% postasphyxial serum with pyrrolidine dithiocarbamate (PDTC). The expression of both BAD and BAX in the cytoplasm was detected by immunohistochemistry. The mitochondria membrane potential (Deltapsim) was examined by confocal microscopy, and the release of the apoptogenic mitochondrial proteins cytochrome C and AIF was assessed by Western blot analysis.. Loss of mitochondria membrane potential was detected in HK-2 cells treated with 20% postasphyxial serum as compared to cells in normal serum or PTDC-pretreated cells in 20% postasphyxial serum. A significant increase of Bad and Bax protein expression was also detected, along with the release of cytochrome C and AIF from mitochondria to cytosol in the postasphyxial serum treated cells, but not in the normal or PTDC-pretreated control cells.. Our findings suggest that postasphyxial serum may induce renal tubular cell apoptosis through the mitochondrial pathway, and its intracellular signal transduction mechanism includes the activation of nuclear factor-kappaB.

Topics: Apoptosis; Asphyxia Neonatorum; bcl-2-Associated X Protein; bcl-Associated Death Protein; Cell Line; Cytochromes c; Cytoplasm; Humans; Immunohistochemistry; Infant, Newborn; Kidney Diseases; Kidney Tubules; Kidney Tubules, Proximal; Membrane Potential, Mitochondrial; NF-kappa B; Pyrrolidines; Reperfusion Injury; Serum; Signal Transduction; Thiocarbamates

In response to ischemic/hypoxic preconditioning, tissues/organs exhibit protective responses to subsequent and severe ischemic stress. We hypothesized that repetitive hypoxic preconditioning (RHP) may provide long-lasting protection than single preconditioning against ischemia/reperfusion injury in rat kidneys through hypoxia-induced factor (HIF)-1-dependent pathway.. For RHP induction, female Wistar rats were subjected to intermittent hypoxic exposure (380 Torr) 15 hr/day for 28 days.. RHP increased renal HIF-1 alpha mRNA and protein expression and triggered HIF-1 alpha-dependent renal Bcl-2 protein expression in a time-dependent manner. When returning to normoxia, increased RHP exposure prolonged renal Bcl-2 expression. Forty-five minutes of renal ischemia with 4 hr of reperfusion enhanced O2- levels and proapoptotic mechanisms, including enhanced cytosolic Bax translocation to mitochondria, release of cytochrome c to cytosol, activation of caspase 3, poly-(ADP-ribose)-polymerase fragments, tubular apoptosis, blood urea nitrogen, and creatinine level. RHP treatment depressed renal O2- production, mitochondrial Bax translocation and cytochrome c release, and tubular apoptosis. In the primary tubular cultures from RHP-treated kidneys, antisense oligodeoxyribonucleotides of bcl-2 abrogated this protection.. RHP activates an HIF-1 alpha-dependent signaling cascade leading to an increase in Bcl-2 protein expression, an inhibition in cytosolic Bax and mitochondrial cytochrome c translocation, and a hypoxic/ischemia tolerance against renal ischemia/reperfusion injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blood Urea Nitrogen; Caspase 3; Cells, Cultured; Creatinine; Cytochromes c; Disease Models, Animal; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Kidney Diseases; Mitochondria; Oligodeoxyribonucleotides, Antisense; Oxidative Stress; Poly Adenosine Diphosphate Ribose; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reperfusion Injury; RNA, Messenger; Signal Transduction; Superoxides; Time Factors; Up-Regulation

Apoptosis and inflammation, important contributors to the progression of chronic kidney disease, can be influenced by clusterin (a secreted glycoprotein that regulates apoptosis) and nuclear factor-kappaB (NF-kappaB, a transcription factor modifying the expression of inflammatory genes). We studied proteinuria-induced renal disease and its influence on clusterin-mediated apoptosis. Exposure of cultured mouse proximal tubule epithelial cells to bovine serum albumin (BSA) resulted in activation of NF-kappaB and activator protein-1 (AP-1) within hours followed by a decline in their activation, decreased activation of extracellular signal-regulated kinases (ERK1/2), decreased cell-associated antiapoptotic Bcl-xL protein but increased apoptosis. Clusterin progressively increased in the media over a 3 day period. Clusterin siRNA blocked protein production, increased NF-kappaB activation, and significantly increased cellular Bcl-xL protein, thereby reducing spontaneous and BSA-induced apoptosis. An siRNA to the NF-kappaB inhibitor IkappaBalpha had similar results. BSA-stimulated NF-kappaB activation reciprocally decreased AP-1 activity by preventing ERK1/2 phosphorylation. These in vitro studies suggest that clusterin inhibits NF-kappaB-mediated antiapoptotic effects by the apparent stabilization of IkappaBalpha switching from promoting inflammation to apoptosis during proteinuria.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Chronic Disease; Clusterin; Cytochromes c; I-kappa B Kinase; Kidney Diseases; Kidney Tubules; MAP Kinase Kinase Kinases; Mice; NF-kappa B; RNA, Small Interfering; Serum Albumin, Bovine; Transcription Factor AP-1; Transcription Factor RelA

Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Depending on its concentration, cisplatin induces necrosis or apoptosis of tubular cells in the kidneys, whereas the underlying injury mechanism is unclear. Our recent work has suggested a critical role for p53 in cisplatin-induced tubular cell apoptosis; nevertheless, the apoptotic events triggered by p53 remain elusive. The current study has examined Bcl-2 family proteins, critical regulators of apoptosis that may be subjected to p53 regulation. Following cisplatin treatment, the expression of Bcl-xL, an antiapoptotic molecule, was suppressed, while the expression of Bak, a proapoptotic molecule, increased slightly. Of interest, PUMA-alpha, a newly identified p53-responsive proapoptotic Bcl-2 family protein, was drastically induced by cisplatin. PUMA-alpha induction preceded or paralleled the development of apoptosis. Induced PUMA-alpha was localized in mitochondria and appeared to antagonize Bcl-xL via molecular interaction. PUMA-alpha induction during cisplatin treatment was attenuated by pifithrin-alpha, a pharmacological inhibitor of p53, which was accompanied by the amelioration of Bax activation, cytochrome c release and apoptosis. Moreover, PUMA-alpha induction was suppressed by dominant-negative p53. Importantly, cisplatin-induced apoptosis was ameliorated in PUMA-alpha knockout cells. In vivo, cisplatin induced PUMA-alpha in the kidneys, and the inductive response was abrogated in p53-deficient animals. Together, this study has demonstrated the first compelling evidence for the involvement of PUMA-alpha in p53-mediated renal cell apoptosis during cisplatin nephrotoxicity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Cell Line; Cisplatin; Cytochromes c; Humans; Kidney Diseases; Kidney Tubules, Proximal; Male; Mice; Mice, Knockout; Mitochondria; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Rats; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Ischemia/reperfusion induces oxidative injury to proximal and distal renal tubular cells. We hypothesize that Bcl-2 protein augmentation with adenovirus vector mediated bcl-2 (Adv-bcl-2) gene transfer may improve ischemia/reperfusion induced renal proximal and distal tubular apoptosis through the mitochondrial control of Bax and cytochrome C translocation. Twenty-four hours of Adv-bcl-2 transfection to proximal and distal tubular cells in vitro upregulated Bcl-2/Bax ratio and inhibited hypoxia/reoxygenation induced cytochrome C translocation, O(2) (-) production and tubular apoptosis. Intra-renal arterial Adv-bcl-2 administration with renal venous clamping augmented Bcl-2 protein of rat kidney in vivo in a time-dependent manner. The maximal Bcl-2 protein expression appeared at 7 days after Adv-bcl-2 administration and the primary location of Bcl-2 augmentation was in proximal and distal tubules, but not in glomeruli. With a real-time monitoring O(2) (-) production and apoptosis analysis of rat kidneys, ischemia/reperfusion increased renal O(2) (-) level, potentiated proapoptotic mechanisms, including decrease in Bcl-2/Bax ratio, increases in caspase 3 expression and poly-(ADP-ribose)-polymerase fragments and subsequent proximal and distal tubular apoptosis. However, Adv-bcl-2 administration significantly enhanced Bcl-2/Bax ratio, decreased ischemia/reperfusion induced O(2) (-) amount, inhibited proximal and distal tubular apoptosis and improved renal function. Our results suggest that Adv-bcl-2 gene transfer significantly reduces ischemia/reperfusion induced oxidative injury in the kidney.

Topics: Adenoviridae; Animals; Apoptosis; Caspases; Cytochromes c; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Kidney Diseases; Kidney Tubules, Distal; Kidney Tubules, Proximal; Oxidative Stress; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reperfusion Injury

Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion and received either minocycline or saline for 36 h before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia as determined by terminal transferase-mediated dUTP nick end-labeling staining and nuclear morphology. It also decreased cytochrome c release into the cytoplasm and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated group showed a significant reduction in tubular injury and cast formation. In addition, minocycline reduced the number of infiltrating leukocytes, decreased leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the minocycline-treated group. We conclude that minocycline has potent antiapoptotic and anti-inflammatory properties and protects renal function in this model of ischemia-reperfusion. Tetracyclines are among the safest and best-studied antibiotics. They are thus attractive candidates for the therapy of human ischemic acute renal failure.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; bcl-2-Associated X Protein; Chemotaxis, Leukocyte; Cytochromes c; Cytosol; Disease Models, Animal; Kidney; Kidney Diseases; Leukocytes; Male; Minocycline; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Suppressor Protein p53; Up-Regulation

Parenteral iron administration is a mainstay of anemia management in renal disease patients. However, concerns of potential iron toxicity persist. Thus, this study was conducted to more fully gauge iron toxicologic profiles and potential determinants thereof.. Isolated mouse proximal tubule segments (PTS) or cultured proximal tubular [human kidney (HK-2)] cells were exposed to four representative iron preparations [iron sucrose (FeS), iron dextran (FeD), iron gluconate (FeG), or iron oligosaccharide (FeOS)] over a broad dosage range (0, 30 to 1000 microg iron/mL). Cell injury was assessed by lactate deyhdrogenase (LDH) release, adenosine triphosphate (ATP) reductions, cell cytochrome c efflux, and/or electron microscopy. In vivo toxicity (after 2 mg intravenous iron injections) was assessed by plasma/renal/cardiac lipid peroxidation [malondialdehyde (MDA)], renal ferritin (protein)/heme oxygenase-1 (HO-1) (mRNA) expression, electron microscopy, or postiron injection PTS susceptibility to attack.. In each test, iron evoked in vitro toxicity, but up to 30x differences in severity (e.g., ATP declines) were observed (FeS > FeG > FeD = FeOS). The in vitro differences paralleled degrees of cell (HK-2) iron uptake. In vivo correlates of iron toxicity included variable increases in renal MDA, ferritin, and HO-1 mRNA levels. Again, these changes appeared to parallel in vivo (glomerular) iron uptake (seen with FeS and FeG, but not with FeD or FeOS). Iron also effected in vivo alterations in proximal tubule cell homeostasis, as reflected by the "downstream" emergence of tubule resistance to in vitro oxidant attack.. Parenteral iron formulations have potent, but highly variable, cytotoxic potentials which appear to parallel degrees of cell iron uptake (FeS > FeG >> FeD or FeOS). That in vitro injury can be expressed at clinically relevant iron concentrations, and that in vivo glomerular iron deposition/injury may result, suggest caution is warranted if these agents are to be administered to patients with active renal disease.

Topics: Animals; Cell Line; Cytochromes c; Dose-Response Relationship, Drug; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; In Vitro Techniques; Infusions, Parenteral; Iron; Iron-Dextran Complex; Kidney; Kidney Cortex; Kidney Diseases; Kidney Tubules, Proximal; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Microscopy, Electron; RNA, Messenger; Severity of Illness Index

Experimental and clinical investigations suggest that oxidant stress is a critical determinant of radiocontrast nephropathy (RCN), and that N acetyl cysteine (NAC) can prevent this damage. This study addresses these issues directly at the tubular cell level. Potential alternative mechanisms for RCN have also been sought.. Isolated mouse proximal tubule segments (PTS), or cultured proximal tubule (HK-2) cells, were subjected to radiocontrast media (RCM) (Ioversol, Optiray 320) exposure, followed by assessments of cellular viability [% lactate dehydrogenase (LDH) release, tetrazolium dye (MTT), uptake] and lipid peroxidation. These experiments were conducted in the absence or presence of a variety of antioxidants [NAC, glutathione (GSH), superoxide dismutase, catalase] or pro-oxidant (GSH depletion, heme oxygenase inhibition) strategies. RCM effects on mitochondrial and plasma membrane integrity were also assessed.. RCM exposure did not induce PTS lipid peroxidation. Neither antioxidant nor pro-oxidant interventions mitigated or exacerbated RCM-induced tubular cell injury, respectively. RCM impaired mitochondrial integrity, as assessed by ouabain-resistant ATP reductions, and by cytochrome c release (before cell death). RCM also induced plasma membrane damage, as indicated by loss of key resident proteins (NaK-ATPase, caveolin) and by increased susceptibility to phospholipase A2 (PLA2) attack (increase of >/=2 times in free fatty acid and NaK-ATPase release). Hyperosmolality could not account for RCM's toxic effects.. RCM toxicity can be dissociated from tubular cell oxidant stress. Alternative mechanisms may include mitochondrial injury/cytochrome c release and plasma membrane damage. The latter results in critical protein loss, as well as a marked increase in plasma membrane susceptibility to exogenous/endogenous PLA2 attack.

Topics: Adenosine Triphosphate; Animals; Caveolin 1; Caveolins; Cell Line; Cell Membrane; Contrast Media; Cytochromes c; Humans; In Vitro Techniques; Kidney Diseases; Kidney Tubules, Proximal; Lipid Peroxidation; Male; Mice; Mice, Inbred Strains; Mitochondria; Ouabain; Oxidative Stress; Phospholipases A; Phospholipases A2; Sodium-Potassium-Exchanging ATPase; Triiodobenzoic Acids