Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of oxidative stress in mercuric chloride (HgCl2)-induced nephrotoxicity is uncertain and controversial. We demonstrate that I.L.C-PK1 cells, exposed to HgCl2, generate massive amounts of hydrogen peroxide, the latter completely quenched by the hydrogen peroxide scavenger, pyruvate. HgCl2 exerts a dose-dependent cytotoxicity which is attenuated by pyruvate and catalase. Cellular generation of hydrogen peroxide arises, at least in part, from mitochondria since mitochondrial rates of generation of hydrogen peroxide increase in response to HgCl2; HgCl2 also provokes a shift in absorbance spectra in rhodamine 123 loaded-mitochondria and stimulates mitochondrial state 4 respiration. HgCl2, applied for one hour, impairs cellular vitality as demonstrated by the MTT assay, an assay dependent in part on mitochondrial function. HgCl2 impairs function in other organelles such as lysosomes that maintain a transmembrane proton gradient; these latter effects are partially attenuated by pyruvate. We complement these in vitro findings with in vivo evidence demonstrating that HgCl2 stimulates renal generation of hydrogen peroxide. The functional significance of such generation of hydrogen peroxide was evaluated in rats deficient in selenium and vitamin E, a nutrient deficiency that impairs the scavenging of hydrogen peroxide and promotes the toxicity of this oxidant. In these rats serum creatinine values were significantly higher on sequential days following the administration of HgCl2. To probe the renal response to oxidative stress induced by HgCl2, we examined hydrogen peroxide-scavenging enzymes and redox-sensitive genes. Catalase activity was unaltered whereas glutathione peroxidase activity was decreased, effects that may contribute to the net renal generation of hydrogen peroxide. The redox sensitive enzyme, heme oxygenase, was markedly up-regulated in the kidney in response to HgCl2. HgCl2 also induced members of the bcl family, bcl2 and bclx, genes that protect against apoptosis and oxidant injury. In another model of oxidant-induced renal injury, the glycerol model, bcl2 mRNA was not induced at 6 and 24 hours after the administration of glycerol. In summary, we demonstrate that HgCl2 potently stimulates renal generation of hydrogen peroxide in vitro and in vivo and such generation of peroxide contributes to renal dysfunction in vitro and in vivo. We also demonstrate that in response to HgCl2, redox sensitive genes are expressed including heme oxygenase and members of the bcl family.
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PMID:Renal oxidant injury and oxidant response induced by mercury. 887 81

To clarify the pathophysiologic role of apoptosis in acute renal failure (ARF), we examined whether the attenuation of cisplatin-induced ARF is associated with the change in the degree of apoptotic cell death. The administration of cisplatin (CDDP) (6 mg/kg body weight) in rats induced ARF at day 5, as manifested by a significant increase in serum creatinine (Scr) and tubular damage. CDDP-induced apoptotic cell death was confirmed by electron microscopic examination, agarose gel electrophoresis, and increased cells positive for TaT-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) in the outer medulla of the kidney. Treatment with dimethylthiourea (DMTU)--a scavenger of hydroxyl radicals--or glycine abrogated CDDP-induced increases in Scr, the tubular damage score, and the number of TUNEL-positive cells. Pretreatment with uranyl acetate (UA) induced a significant expression of Bcl-2 in the kidney and ameliorated CDDP-induced increases in Scr, the tubular damage score, and TUNEL-positive cells in the outer stripe of the outer medulla. Our findings indicate (1) that the attenuation of CDDP-induced ARF was associated with less apoptotic cell death and (2) that the induction of the anti-apoptotic protein Bcl-2 attenuated apoptosis and tubular damage. Our results suggest that apoptotic cell death may play an important role in the development of cisplatin-induced ARF.
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PMID:Attenuation of cisplatin-induced acute renal failure is associated with less apoptotic cell death. 1059 94

Growth retardation is a complication often associated with corticosteroid therapy. Corticosteroids are frequently used in the treatment of children with chronic renal failure. To examine the effects of corticosteroids on the growth plate cartilage in renal failure, selected markers of chondrocyte function and phenotype were evaluated in the proximal tibia of subtotally nephrectomized rats treated with corticosteroid. Serum parathyroid hormone (PTH), urea nitrogen, and creatinine levels were higher in the nephrectomized animals. Weight gain was less in the corticosteroid-treated animals; however, linear growth and tibial length did not differ among the groups after 10 days of corticosteroid therapy. The total width of the growth plate and the width of the proliferative zone were much smaller in corticosteroid-treated nephrectomized (Nx-MP) animals. Type II collagen mRNA expression was lower in animals treated with corticosteroids, and proliferating-cell nuclear antigen staining, histone-4, and insulin-like growth factor-1 (IGF-1)-receptor mRNA expression were further decreased in the Nx-MP group. There was an increase in TUNEL-positive cells in the corticosteroid-treated rats with normal renal function (intact-MP), associated with an increase in Bax and a decrease in Bcl-2 protein expression. In the Nx-MP group, both Bax and Bcl-2 protein staining was much less frequent, and TUNEL-positive cells were lower in number compared with the intact-MP group. Vascular endothelial growth factor expression in the hypertrophic chondrocytes was lower in corticosteroid-treated animals. There was less gelatinase B/matrix metalloproteinase-9 expression in the Nx-MP group, which was not associated with a decrease in tartrate-resistant acid phosphatase (TRAP) staining in the chondro-osseous junction. Inhibition of chondrocyte proliferation, diminishing of apoptosis, and lower angiogenic activity may contribute to the alterations in growth plate architecture and the significant reduction in growth plate width in rats with renal failure receiving corticosteroid therapy.
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PMID:Alterations in the growth plate cartilage of rats with renal failure receiving corticosteroid therapy. 1199 6

Colchicine has been shown to prevent kidney injury in chronic cyclosporine nephrotoxicity; however, the mechanisms of its action are undetermined. The purpose of this study was to clarify whether colchicine prevents cyclosporine-induced kidney injury by decreasing kidney-cell apoptosis. We also sought to determine whether such an antiapoptotic effect was related to Bcl-2/Bax protein and caspase3 activity. Adult male Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 28 days with cyclosporine (15 mg/kg in 1 mL/kg olive-oil vehicle), colchicine (30 microg/kg in 100% ethanol, diluted with sterile saline solution to a final concentration of 30 microg/mL), or both cyclosporine and colchicine. Kidney function, histomorphologic findings, in situ terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end-labeling assay, expressions of Bcl-2 and Bax proteins, and caspase-3 enzymatic activity were compared for the different treatment groups. Compared with the vehicle-treated rats, rats given cyclosporine showed a decline in creatinine clearance rate, an increase in serum creatinine concentration, tubulointerstitial fibrosis, and an increase in the number of apoptotic cells (all P <.01). Concomitant administration of colchicine significantly reversed all the above parameters (all P <.05). The decreased expression of Bcl-2 and the ratio of Bcl-2 to Bax protein seen in cyclosporine-treated rat kidneys were significantly increased after colchicine treatment, accompanying a suppression of caspase-3 activity (P <.05). Furthermore, the decreased apoptotic cell death was closely correlated with improved renal tubulointerstitial fibrosis (r = 0.583, P <.05). These findings strongly suggest that a renoprotective effect of colchicine on cyclosporine-induced nephrotoxicity is coassociated with a decrease in apoptotic cells.
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PMID:Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity. 1206 35

H1-A, a pure compound used in traditional Chinese medicine, is effective in the treatment of autoimmune disorders of MRL lpr/lpr mice. We have previously reported that after 8 weeks of oral therapy with H1-A, 40 microg/kg/day, MRL lpr/lpr mice demonstrated significantly less proteinuria, lower serum creatinine levels, and less renal mesangial proliferation than mice in an untreated group. To clarify the pharmacologic properties of H1-A, we studied its cellular and subcellular effects in cultured human mesangial cells. Our results show that H1-A inhibits cell proliferation and promotes the apoptosis of interleukin (IL)-1- and platelet-derived growth factor (PDGF)-BB-activated human mesangial cells in vitro. Uptake of tritiated thymidine was nearly totally suppressed by the addition of 12.5 micromol/L H1-A (counts per minute decreased from 3905 +/- 70 to 141 +/- 5). The population of S-phase cells decreased from 15.5% +/- 1.7% to 10.0% +/- 0.3%, and G0 + G1 phase cells increased from 68.8% +/- 0.07% to 74.6% +/- 0.05%. This suppression was not a result of cytotoxicity. Apoptosis of human mesangial cells was detectable after treatment with 12.5 or 25 micromol/L H1-A. Using immunoprecipitation and immunoblotting, we found that H1-A inhibits tyrosine phosphorylation of human mesangial proteins and that Bcl-2 and Bcl-XL were probably among these proteins. These findings suggest that H1-A modulates some subcellular signal-transduction pathways and changes the balance between proliferation and apoptosis of mesangial cells in vitro or in vivo. H1-A may be effective in the management of autoimmune disorders, and the modulation of the signal transduction proteins Bcl-2 and Bcl-XL may represent a target for future pharmacologic interventions.
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PMID:H1-A extracted from Cordyceps sinensis suppresses the proliferation of human mesangial cells and promotes apoptosis, probably by inhibiting the tyrosine phosphorylation of Bcl-2 and Bcl-XL. 1251 71

The extent of graft damage after ischemia-reperfusion reflects the balance between deleterious events and protective factors. Heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) may contribute to cytoprotection by their anti-inflammatory and antiapoptotic properties. For investigating whether HO-1 and VEGF play a role in the adaptive response to ischemia-reperfusion injury after renal transplantation, kidney biopsies were analyzed from living (n = 45) and cadaveric (n = 16) donors, obtained at three time points: at the end of cold storage T(-1), after warm ischemia T(0), and after reperfusion T(+1). The mRNA expression levels of HO-1, VEGF(165), Bcl-2, Bax, and hypoxia inducible factor-1alpha were quantified by real-time reverse transcriptase-PCR, and the HO-1 and VEGF proteins were analyzed by immunohistochemistry. Cadaveric donor kidneys presented higher mRNA expression levels of hypoxia inducible factor-1alpha. In contrast, mRNA expression levels of HO-1, VEGF(165), and Bcl-2 were significantly lower in kidneys from cadaveric donors. Overall, a significant correlation was observed between mRNA expression of Bcl-2 and VEGF(165), between Bcl-2 and HO-1, and between HO-1 and VEGF(165). Moreover, protein expression of HO-1 and VEGF was detected in the same anatomical kidney compartments (glomerulus, arteries, and distal tubules). Renal function at the first week posttransplantation (analyzed by serum creatinine levels) showed a significant correlation with both HO-1 and VEGF mRNA expression, reinforcing the protective role of both genes in the early events of transplantation. It is concluded that the lower expression of HO-1, VEGF(165), and Bcl-2 in cadaveric donor kidneys can reflect a defective adaptation against ischemia-reperfusion injury that may affect their function in the short term.
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PMID:Differential expression of heme oxygenase-1 and vascular endothelial growth factor in cadaveric and living donor kidneys after ischemia-reperfusion. 1463 27

Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.
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PMID:Downregulation of Bcl-2 by podocytes is associated with progressive glomerular injury and clinical indices of poor renal prognosis in human IgA nephropathy. 1469 60

The peripheral benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell death. In the present study we investigated the role of PBR in the regulation of signaling pathways leading to apoptotic and necrotic damage and renal dysfunction in a rat model of ischemia-reperfusion. Renal ischemia-reperfusion led to extended tubular apoptosis and necrosis that were associated with peroxidative damage, high levels of proapoptotic Bax expression, and low levels of antiapoptotic Bcl-2 expression, cleavage of death substrate, poly(ADP-ribose) polymerase (PARP), and activation of a key effector of apoptosis, caspase-3. Rat pretreatment with a novel PBR antagonist, SSR180575, significantly decreased postreperfusion oxidative stress and tubular apoptosis and necrosis. This effect was associated with inhibition of caspase-3 activation and PARP cleavage, upregulation of Bcl-2, and downregulation of Bax. Furthermore, inhibition of PBR accelerated the recovery of normal renal function, as assessed by measurement of levels of plasma creatinine and blood urea nitrogen. These findings reveal a role for PBR as a modulator of necrotic and apoptotic cell death induced by ischemia-reperfusion and suggest that regulation of PBR may provide new therapeutic implications for the prevention of acute renal failure.
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PMID:Involvement of peripheral benzodiazepine receptor in the oxidative stress, death-signaling pathways, and renal injury induced by ischemia-reperfusion. 1528

Tubular cell apoptosis is involved in ischemic renal failure, but the underlying mechanism is unclear. Bid, a proapoptotic Bcl-2 family protein, may regulate the intrinsic as well as the extrinsic pathway of apoptosis. In vivo, Bid is most abundantly expressed in the kidneys. However, the role played by Bid in renal pathophysiology is unknown. Our recent work demonstrated Bid activation during renal ischemia-reperfusion. The current study has determined the role of Bid in ischemic renal injury and renal failure using Bid-deficient mice. In wild-type C57BL/6 mice, Bid was proteolytically processed into active forms during renal ischemia-reperfusion, which subsequently targeted mitochondria. This was accompanied by the development of tissue damage and severe renal failure, showing serum creatinine of 3.0 mg/dl after 48 h of reperfusion. The same ischemic insult induced acute renal failure in Bid-deficient mice, which was nonetheless less severe than the wild-type, showing 1.3 mg/dl serum creatinine. In addition, Bid deficiency attenuated tubular disruption, tubular cell apoptosis, and caspase-3 activation during 48 h of reperfusion. Compared with wild-type, animal death following renal ischemia was delayed in Bid-deficient mice. Collectively, the results suggest a role for Bid in ischemic renal injury and renal failure.
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PMID:Bid deficiency ameliorates ischemic renal failure and delays animal death in C57BL/6 mice. 1610 37

Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.
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PMID:Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. 1659 97


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