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)

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

HGF is a multifunctional polypeptide with mitogenic, motogenic and morphogenic effects. These effects are mediated by c-met, a specific receptor of HGF and a member of the receptor tyrosine kinase superfamily, virtually expressed in every type of kidney cell. HGF has a central role during embryogenesis since it stimulates epithelial differentiation of metanephric mesenchymal cells and induces branching tubules, as experiments in epithelial cells cultures demonstrated. Several studies have shown also that HGF accelerates the recovery from toxic-ischemic acute renal failure. This effect seems to be mediated by the inhibition of programmed cell death and an increased cell survival. HGF inhibits apoptosis by upregulating the protooncogene Bcl-2 and downregulating Bax. Since HGF can modulate extracellular matrix turnover, authors suggest its beneficial role in tissue remodelling and particularly in chronic renal diseases. Several studies reported a key role for HGF in reducing interstitial fibrosis and glomerular sclerosis, both in in vivo and in vitro models. This protective effect is secondary to HGF antagonizing the profibrotic action of TGF-beta. HGF modulates the balance between synthesis and degradation of extracellular matrix, increasing the expression of metalloproteases and reducing the production of their specific inhibitors TIMPs. Furthermore HGF suppresses the effect of TGF-beta by blocking the axis TGF-beta/Smad. Last, the antifibrotic effect of HGF might be modulated by the proliferative status of target cells. To sum up, the supplementation of exogenous HGF or the induction of endogenous HGF expression may provide an effective therapeutic strategy for combating chronic renal diseases.
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PMID:[Hepatocyte growth factor and kidney]. 1706 38

Bid, a BH3-only member of the Bcl-2 family proteins, is most abundantly expressed in the kidneys. Recent research has shown Bid activation in renal tubular cells in vitro following ATP-depletion and hypoxic injury, and also in vivo during renal ischemia-reperfusion in rats and mice. Importantly, Bid-deficient mice are resistant to ischemic kidney injury. Targeting Bid may therefore offer a new strategy for the treatment of acute renal failure associated with ischemia-reperfusion.
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PMID:Regulation and pathological role of bid in ischemic acute kidney injury. 1806 37

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-tumor action in a variety of cancer cells. However, several treatment side effects such as gastrointestinal injury, cardiovascular toxicity, and acute renal failure limit their clinical use. We found that indomethacin caused renal epithelial cell injury independently of cyclooxygenase inhibition. Indomethacin treatment was associated with the disruption of mitochondrial transmembrane potential, release of cytochrome c, down-regulation of Bcl-2 and Mcl-1, upregulation of Bax, and elevation of caspases activity. Enhanced Mcl-1 but not Bcl-2 expression alleviated indomethacin-increased caspase-3 activity. Down-regulation of Akt-related and signal transducer and activator of transcription (STAT-3)-related pathways was found in indomethacin-treated cells. Pharmacological and genetic studies revealed a potential mechanistic link between Akt/Mcl-1 and STAT-3/Mcl-1 signaling pathways and indomethacin-induced cytotoxicity. Mcl-1 is a determinant molecule for the induction of epithelial cell injury caused by indomethacin. Therefore, the maintenance of Mcl-1 levels is important for prevention of renal epithelial cell injury and apoptosis.
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PMID:Indomethacin causes renal epithelial cell injury involving Mcl-1 down-regulation. 1925 Jun 43

Shiga toxins (Stxs), which are proteins expressed by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli, are potent protein synthesis inhibitors. Stx-producing organisms cause bloody diarrhea with the potential to progress to acute renal failure and central nervous system complications. Studies using animal models of these diseases have shown that Stxs are major virulence factors, and purified toxins have been shown to be capable of killing many types of cells in vitro. We showed that Stx type 1 (Stx1) rapidly induced apoptosis in undifferentiated, monocytic THP-1 cells through a mechanism involving the endoplasmic reticulum (ER) stress response. Rapid apoptosis correlated with increased expression of C/EBP homologous protein (CHOP), TRAIL, and DR5, while expression of the antiapoptotic factor Bcl-2 was downregulated. Stx1 treatment of differentiated, macrophage-like THP-1 cells was associated with cytokine production and delayed apoptosis. The mechanisms contributing to cell maturation-dependent differences in responses to Stx1 are unknown. We show here that in macrophage-like cells, Stx1 activated the proximal ER stress sensors RNA-dependent protein kinase-like ER kinase and inositol-requiring ER signal kinase 1alpha but did not activate activating transcription factor 6. Proapoptotic signaling pathways mediated by CHOP and by Bax and Bak were activated by Stx1. However, the toxin also activated prosurvival signaling through increased expression, mitochondrial translocation, and alternative phosphorylation of Bcl-2.
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PMID:Bcl-2 regulates the onset of shiga toxin 1-induced apoptosis in THP-1 cells. 1975 28

Cisplatin (CDDP), a major chemotherapeutic agent used to treat solid tumors, is known to induce acute renal failure (ARF). The progression of tissue injury involves the coordination of inflammatory and repair responses. Interleukin-6 (IL-6) has been suggested to modulate inflammatory and repair processes in various tissue injuries. In this study, we analyzed IL-6 regulation during CDDP-induced ARF in wild-type (WT) mice and determined the pathological role of IL-6 using IL-6 knockout ((-/-)) mice. A correlation between increase in serum IL-6 level and blood urea nitrogen level was found in WT mice. Renal IL-6 expression in most proximal tubular cells and suppressor of cytokine signaling 3 (SOCS3) gene expression significantly increased in WT mice after administration of CDDP, suggesting active IL-6 signaling during CDDP-induced ARF development. Interestingly, renal dysfunction occurred soon after administration of CDDP and became more severe in IL-6(-/-) mice than that in WT mice. In contrast, the survival rate of IL-6(-/-) mice (50% at 8 days) was better than that of WT mice (10%). Induction levels of proapoptotic Bcl-2 associated X protein (Bax) in renal proximal tubular cells was significantly higher in IL-6(-/-) mice than in WT mice at 24h after CDDP injection. Levels of antiapoptotic proteins, Bcl-2 and Bcl-extra large (Bcl-x(L)), in IL-6(-/-) groups were significantly higher than those in CDDP-treated WT groups throughout the experimental period. Bax might contribute to the development of CDDP-induced ARF at 24h; however, high expression levels of Bcl-x(L) and Bcl-2 might overcome the proapoptosis signaling at 72 h in IL-6(-/-) mice. These results indicated that local and systemic elevation of IL-6 contributes to the development of CDDP-induced ARF and that IL-6 produced in renal tubular cells prevents progression of ARF at the early stage. IL-6 deficiency accelerates CDDP-induced ARF but not development of systemic injury.
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PMID:Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury. 1983 67

We recently reported that the expression of the synaptic form of acetylcholinesterase (AChE) is induced during apoptosis in various cell types in vitro. Here, we provide evidence to confirm that AChE is expressed during ischemia-reperfusion (I/R)-induced apoptosis in vivo. Renal I/R is a major cause of acute renal failure (ARF), resulting in injury and the eventual death of renal cells due to a combination of apoptosis and necrosis. Using AChE-deficient mice and AChE inhibitors, we investigated whether AChE deficiency or inhibition can protect against apoptosis caused by I/R in a murine kidney model. Unilateral clamping of renal pedicles for 90 min followed by reperfusion for 24 h caused significant renal dysfunction and injury. Both genetic AChE deficiency and chemical inhibition of AChE (provided by huperzine A, tacrine and donepezil) significantly reduced the biochemical and histological evidence of renal dysfunction following I/R. Activation of caspases-8, -9, -12, and -3 in vivo were prevented and associated with reduced levels of cell apoptosis and cell death. A further investigation also confirmed that AChE deficiency down-regulated p53 induction and phosphorylation at serine-15, and decreased the Bax/Bcl-2 ratio during I/R. In conclusion, our study demonstrates that AChE may be a pro-apoptotic factor and the inhibition of AChE reduces renal I/R injury. These findings suggest that AChE inhibitors may represent a therapeutic strategy for protection against ischemic acute renal failure.
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PMID:AChE deficiency or inhibition decreases apoptosis and p53 expression and protects renal function after ischemia/reperfusion. 2005 52

Renal ischaemia-reperfusion injury (IRI) is consecutive to tissue oxidative damage and cell apoptosis that lead to acute renal failure (ARF) in renal allografts. The aim of this study was to investigate the beneficial effects of a pretreatment by clopidogrel on renal IRI in mice. IRI was induced by bilateral renal ischaemia for 45 min followed by reperfusion. Sixty-two healthy male BALB/c mice were randomly assigned to one of the following groups: PBS + ischaemia-reperfusion (IR); clopidogrel + IR; PBS + sham IR; clopidogrel + sham IR. Clopidogrel (25 mg/kg) or PBS was administered per os to the animals via a gastric cannula 24 h before operation. All mice were given a single dose of clopidogrel or PBS. Renal function histological damage, renal cell apoptosis, renal antioxidant activities, and CD41 expression were determined 24 h after reperfusion. The survival rates were evaluated over 7 days. Animals pretreated with clopidogrel had lower plasma levels of blood urea nitrogen (BUN) and creatinine, lower histopathological scores, and improved survival rates following IR. Renal cell apoptosis induced by IR was decreased in kidneys of mice pretreated by clopidogrel, with an increase in Bcl-2 and Bcl-xL expression and a decrease in caspase-3, caspase-8, and Bax expression. Renal reduced glutathione, superoxide dismutase, and catalase activities were unmodified by the pretreatment with clopidogrel. However, clopidogrel resulted in an increased total antioxidant capacity of the kidney. Furthermore, pretreatment by clopidogrel decreased the number of CD41-positive cells. Thus, clopidogrel exerts protective effects on renal IRI in mice by abrogating renal cell apoptosis as a consequence of improved renal antioxidant capacity and could be tried as a novel therapeutic tool in renal IRI.
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PMID:Clopidogrel protects from cell apoptosis and oxidative damage in a mouse model of renal ischaemia-reperfusion injury. 2163 Feb 70

Oxidative stress is a major mediator of tissue and cell injuries. The injury in chronic nephrotic syndrome, acute renal failure, myeloma kidney injury and other kidney diseases is initiated by oxidative stress. We have previously demonstrated that vasoactive intestinal peptide (VIP) acts as an antiproliferative agent in renal cancer cells. This study was designed to evaluate the renoprotective activity of VIP against H(2)O(2)-induced oxidative damage in a proximal tubule kidney cell line (human, non-tumor, HK2 cells) in order to investigate the potential usefulness of this peptide in the treatment of oxidative-stress related kidney diseases. HK2 cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Propidium iodide was used to identify cells undergoing apoptosis. Western blotting was performed with anti-Bcl-2, anti-Bax and anti-formyl peptide receptor (low-affinity variant FPRL-1) monoclonal antibodies whereas 2,7-dichlorofluorescein diacetate was used for measurement of levels of intracellular reactive oxygen species (ROS). HK2 cells were injured with H(2)O(2) in order to induce apoptosis: the effect was time- and dose-dependent. VIP increased the levels of the antiapoptotic protein Bcl-2 and decreased those of the proapoptotic protein Bax. VIP decreased the intracellular ROS levels reached by H(2)O(2)-induced oxidative stress. VIP effect on ROS levels involved FPLR-1 but not VPAC(1,2) receptors as evidenced by the use of the respective antagonists WRW4 and JV-1-53. Thus, VIP protects HK2 cells from apoptosis by increasing Bcl-2 levels and this effect is initiated through FPLR1 receptor. In conclusion, VIP might exert a renoprotective effect by the suppression of oxidative stress.
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PMID:Antioxidant activity of vasoactive intestinal peptide in HK2 human renal cells. 2300 Mar 5


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