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PubMed2004

Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer.

Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.

Antineoplastic Agents↗
PubMed2004

[Induction of monocyte chemoattractant protein-1 expression in human mesangial cells by angiotensin II: role of c-Jun N-terminal kinase-c-Jun/activator protein-1 signal pathway].

OBJECTIVE: To investigate the role of c-Jun N-terminal kinase (JNK)-c-Jun/activator protein-1 (AP-1) signal pathway in expression of monocyte chemoattractant protein-1 (MCP-1) in experimental rat glomerulonephritis. METHODS: Nephrotoxic sera nephritis (NTN) was induced by injection of anti-GBM antibody into the tail veins of rats. Electrophoretic mobility shift assay (EMSA) and non-radioactive kinase assay were used to detect the activity of AP-1 and JNK in kidneys and angiotensin II-stimulated human mesangial cells. Ribonuclear protection assay was used to detect MCP-1 expression in cultured human mesangial cells. RESULTS: Significant up-regulation of JNK and AP-1 was observed in NTN rats (3.82 +/- 0.58) folds and (5.36 +/- 0.61) folds, as compared with the controls. Supershift assay demonstrated that c-Jun and c-Fos were the predominant subunits involved. Activation of JNK and AP-1 significantly correlated with MCP-1 expression in NTN rats. Angiotensin II enhanced the expression of MCP-1 and activation of JNK and AP-1 in cultured human mesangial cells in a dose-dependent manner, with maximal stimulation seen at 100 nmol/L (20.99 +/- 4.71) folds, (6.91 +/- 1.65) folds and (7.82 +/- 1.32) folds respectively. Significant down-regulation of AP-1 activation and MCP-1 expression were observed in angiotensin II-induced human mesangial cells pretreated with JNK specific inhibitor SP600125. CONCLUSIONS: Angiotensin II and MCP-1 may play an important role in glomerulosclerosis via the JNK-c-Jun/AP-1 signal pathway.

Angiotensin II↗
PubMed2004

Prostaglandin E2 selectively antagonizes prostaglandin F2alpha-stimulated T-cell factor/beta-catenin signaling pathway by the FPB prostanoid receptor.

FP prostanoid receptors are G-protein-coupled receptors that consist of two isoforms named FPA and FPB. Both isoforms activate inositol phosphate second messenger signaling pathways by their endogenous ligand prostaglandin F2alpha (PGF2alpha). Previously we have shown that both isoforms undergo Rho-mediated cell rounding following treatment with PGF2alpha. Following the removal of PGF2alpha, however, FPA-expressing cells return to their original morphology, whereas FPB-expressing cells do not. It was also found that PGF2alpha-could activate T-cell factor (Tcf)/beta-catenin signaling in cells expressing the FPB isoform but not in cells expressing the FPA isoform. We now show that prostaglandin E2 (PGE2) can induce cell rounding and stimulate the formation of inositol phosphates to the same extent as PGF2alpha in cells expressing either the FPA or FPB isoforms. However, PGE2 has much lower efficacy as compared with PGF2alpha for the activation of Tcf/beta-catenin signaling in FPB-expressing cells, and the cell rounding is reversible. Interestingly, pretreatment of FPB-expressing cells with PGE2-attenuated PGF2alpha-stimulated Tcf/beta-catenin signaling in a dose-dependent manner while having no effect on PGF2alpha-stimulated inositol phosphates formation. Thus, the ratio of endogenous PGE2 and PGF2alpha has the potential to selectively regulate one signaling pathway over another. This represents a novel mechanism for the regulation of cell signaling that is distinct from regulation occurring at the level of the receptor and its effector pathways.

Cell Line↗
PubMed1999

Signalling pathways in the brain: cellular transduction of mood stabilisation in the treatment of manic-depressive illness.

The long-term treatment of manic-depressive illness (MDI) likely involves the strategic regulation of signalling pathways and gene expression in critical neuronal circuits. Accumulated evidence has identified signalling pathways, in particular the family of protein kinase C (PKC) isozymes, as targets for the long-term action of lithium. Chronic lithium administration produces a reduction in the expression of PKC alpha and epsilon, as well as a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. More recently, studies have demonstrated robust effects of lithium on another kinase system, GSK-3beta, and on neuroprotective/neurotrophic proteins in the brain. Given the key roles of these signalling cascades in the amplification and integration of signals in the central nervous system, these findings have clear implications not only for research into the neurobiology of MDI, but also for the future development of novel and innovative treatment strategies.

Adult↗
PubMed2000

Differential requirements of the MAP kinase and PI3 kinase signaling pathways in Src- versus insulin and IGF-1 receptors-induced growth and transformation of rat intestinal epithelial cells.

There have been few studies on the specific signaling pathways involved in the transformation of epithelial cells by oncogenic protein tyrosine kinases. Here we investigate the requirement of MAP (MAPK) and phosphatidylinositol 3- (PI3K) kinases in the transformation of rat intestinal epithelial (RIE) cells by oncogenic forms of insulin receptor (gag-IR), insulin-like growth factor-1 receptor (gag-IGFR), and v-Src. MAPK is not significantly activated in cells transformed by gag-IR and gag-IGFR but is activated in v-Src transformed cells. Treatment with PD98059, a MEK inhibitor, at concentrations where MAPK activity was reduced below the basal level showed that MAPK is partially required for the monolayer growth of parental and transformed RIE cells. However, MAPK is not essential for the focus forming ability of the three oncogene-transformed cells. It is also not necessary for the colony forming ability of gag-IR- and gag-IGFR-, but is partially required for v-Src-transformed cells. PI3K is significantly activated in all three oncogene transformed RIE cells. LY294002, a PI3K inhibitor, potently inhibited monolayer growth of all three oncogene-transformed cells. However, at concentrations of LY294002 where activated forms of Akt, a downstream component of the PI3K pathway, were undetectable, colony and focus forming abilities of the v-Src-RIE cells were only slightly affected whereas those of gag-IR/IGFR-RIE cells were greatly inhibited. These results were confirmed using a different pharmacological inhibitor, wortmannin, and a dominant negative form of PI3K, Ap85. Similarly, rapamycin, known to inhibit p70S6 kinase, a downstream component of the PI3K-Akt pathway, also inhibited gag-IR/IGFR-induced, but not v-Src-induced, focus and colony formation. We conclude that the MAPK and PI3K signaling pathways are differentially required for transformation of RIE cells by oncogenic IR and IGFR versus Src and the pattern of requirements is different from that of fibroblast transformation.

Androstadienes↗
PubMed1997

Cross-talk between phospholipase C and phosphoinositide 3-kinase signalling pathways.

1321N1 astrocytoma cells have proved a valuable model system in which to study interactions between two major PtdIns (4,5) P2-utilizing signaling pathways, since they possess receptor populations which elicit independent activation of PI 3-kinase and a G-protein-dependent PLC respectively. Activation of PLC down-regulates PI 3-kinase by at least two mechanisms involving inhibition of IRS-1-associated PI 3-kinase and acute activation of a PtdIns (3,4,5) P3 5-phosphatase. PKB, which is an important early PI 3-kinase-dependent component of insulin signalling pathways, is also down-regulated by PLC-coupled agonists. The activation of PKB by insulin appears to involve a novel PtdIns (3,4,5) P3-dependent protein kinase, which we have named PDK1. The molecular mechanisms underlying PtdIns (3,4,5) P3-stimulated phosphorylation and activation of PKB by PDK1 are currently under investigation.

Animals↗
PubMed2004

Signaling pathways for Fc gamma receptor-stimulated tumor necrosis factor-alpha secretion and respiratory burst in RAW 264.7 macrophages.

Fc gamma receptor (Fc gammaR) signaling mediates several important macrophage functions including cytokine secretion and respiratory burst. The present study describes the development of a model using the macrophage cell line, RAW 264.7 for studying Fc gammaR-stimulated tumor necrosis factor-alpha (TNF-alpha) secretion and hydrogen peroxide (H2O2) production. In unprimed cells these functions were low but pretreatment with interferon-gamma augmented Fc gammaR-stimulated TNF-alpha secretion and H2O2 production to levels that were about half that caused by lipopolysaccharide (LPS) and zymosan, respectively. Studies on the signaling pathways found that TNF-alpha secretion stimulated by either Fc gammaR or LPS was decreased by inhibitors of PKC, MAPK p42/p44, and MAPK p38. TNF-alpha secretion was also reduced by the combination of PLC and PLD inhibitors but not by the individual inhibitors alone. H2O2 production stimulated by either Fc gammaR or zymosan was blocked by inhibitors of PKC, PLC, PLD, and MAPK p42/44 but not by MAPK p38. Thus, interferon-gamma treated RAW 264.7 cells are a model of inflammatory macrophages and are well suited for further study of these signaling pathways.

Animals↗
PubMed2005

[High glucose regulates the production of MMP-9 in podocyte through ERK1/2 signal pathway].

OBJECTIVE: To assess the effect of high glucose on the production of gelatinase and collagen alpha (IV) protein in podocytes and its possible signal pathway. METHODS: Mouse podocytes of an immortalized cell line were cultured and divided into 3 groups: NG group, treated with normal concentration of D-glucose (100 mg/dl), HG group, treated with high concentration of D-glucose (450 mg/dl), and MN group, treated with mannitol (350 mg/dl) plus D-glucose (100 mg/dl). The culture medium supernatants were collected every day. The activity of MMP-9 and MMP-2 was detected by gelatin zymography, the level of collagen alpha5 (IV) protein and the activation of MAPKs (Erk, p38, and JNK) signaling pathway in podocytes were detected by Western blot analysis, and the level of MMP-9 mRNA was detected by RT-PCR. Another podocytes were pretreated by PD9805, a specific inhibitor of MEK1 activation, and then divided into 3 groups as mentioned above so as to detect the effects of high glucose on the MMP-9 activation, and expression of MMP-9 mRNA and collagen alpha5 (IV) protein. RESULTS: The MMP-2 and MMP-9 activity in the medium supernatants of the NG and MN groups remained constant during the 10 days' incubation. High glucose incubation also did not affect the activity of MMP-2. The MMP-9 activity in the supernatant of the HG group began to increase in the 2nd day, reached the maximum in the 3rd day (144.2 +/- 18.1% that of the NG group, P = 0.006), then began to decline since the 5th day, back to the basal level in the 7th day (76.6 +/- 16.4% that of the NG group, P = 0.218), and remained at the basal level until the 10 th day. The basal level of collagen alpha5 (IV) protein in the supernatant of the NG group was quite high. The collagen alpha5 (IV) protein level in the supernatant of the HG group began to decrease since the 2nd day, reached the minimum in the 3rd day (41.9 +/- 25.5% that of the NG group, P = 0.047), then backed to the basal levels in the 5th day, and retained at that level to the 7th days. The MMP9 activity in the supernatant of the HG group had a strongly negative correlation with the levels of collagen alpha5 (IV) protein (r = -0.577, P < 0.006). The levels of collagen alpha5 (IV) protein in the supernatant of NG and MN groups showed no significant change during the 7 days' incubation. The level of MMP-9 mRNA of the HG group was 199.8 +/- 40.2% that of the NG group (P = 0.003) 2 days after stimulation, and was 90.9 +/- 8.8% that of the NG group 5 days after incubation (P = 0.411). Phosphorylation of ERK1/2 occurred as early as 30 min after simulation by high glucose, reached the peak level 6 hours later, remained at this level for 24 hours, then backed to the basal level 48 hours later, whereas the activation of p38 and JNK remained undetectable. Pretreatment with PD98059, for 30 min abolished the HG-stimulated increase of MMP-9 activity and MMP-9 mRNA, as well as the decrease of collagen alpha5 (IV) protein. CONCLUSION: The production of MMP-9 and the levels of collagen alpha5 (IV) protein can be regulated by high glucose, and the ERK1/2 transduction pathway mediate such regulation.

Animals↗
PubMed2000

An SPR-based screening method for agonist selectivity for insulin signaling pathways based on the binding of phosphotyrosine to its specific binding protein.

A new screening method was developed that evaluates physiologically relevant chemical selectivity of agonists for insulin-signaling pathways. Phosphorylation (pY939) by an insulin-activated insulin receptor of a target peptide (Y939) derived from an insulin receptor substrate-1 (IRS-1) and its subsequent binding to another downstream target, the SH2 domain of PI-3 kinase (SH2N), were detected by surface plasmon resonance (SPR) spectrometry. This method is based on competitive binding of SH2N to pY939 either in a solution or on the gold surface of the SPR sensor chip. With increasing the concentration of pY939 in solution by the insulin-induced kinase reaction of insulin receptor, SH2N bound to pY939 in solution increases and the one on the sensor chip decreases, thereby causing a decrease in the SPR signal. The amount of thus-detected complex pY939-SH2N was found to depend on added insulin concentrations, confirming that the method utilized part of the sequential transduction mechanism of the insulin-signaling pathways. The kinase activity of insulin receptor-agonist complexes increased in the order of IGF-II < IGF-I < insulin, and neither vanadium ions nor thiazolidine-type medicines for NIDDM, troglitazone and pioglitazone, directly acted on both the kinase reaction of insulin receptor or the binding of pY939 to SH2N. The present approach will thus become a general method for screening agonists for one specific pathway in tyrosine phosphorylation of IRS-1 in insulin signaling, which is regulated by specific protein-protein interaction between a phosphorylated tyrosine in IRS-1 and its corresponding SH2 domain-containing protein such as PI-3 kinase, Grb2-Sos, or SHP2.

Animals↗
PubMed2001

The ras signaling pathway in mammary tumorigenesis and metastasis.

The Ras superfamily of GTPases act as important regulatory switches to co-ordinate extracellular stimuli with activation of intracellular signaling pathways and appropriate biological responses. The Ras branch of this superfamily includes H-, K- and N-Ras, which are commonly mutated in particular human cancers, but notably not in those of the breast. Instead, in breast cancer the signaling pathways involving these GTPases may be upregulated due to increased coupling to growth factor receptors or other tyrosine kinases commonly overexpressed in this disease, or increased expression of regulators, the Ras protein itself, or downstream effectors. Functional studies utilizing both in vitro and in vivo models demonstrate that Ras signaling can regulate a variety of endpoints relevant to breast cancer progression, including anchorage dependent and independent growth, tumorigenesis, steroid sensitivity and invasion. Finally, analysis of the processing and signaling mechanisms of the Ras superfamily has identified potential targets for therapeutic intervention.

Animals↗
PubMed1997

Intracellular signal pathways controlling respiratory neurons.

Medullary respiratory neurons are influenced by a variety of neuromodulators, but there is a lack of information about the specific intracellular signal pathways involved. In this report we describe the modulatory effects of the cyclic adenosine-triphosphate (cAMP)-dependent protein kinase and of protein kinase C pathways on voltage- and ligand-controlled ionic conductances and demonstrate their functional significance in regulating the excitability of medullary respiratory neurons of the vivo cat. Evidence is presented that PKA and PKC pathways are persistently activated. PKA regulates current flow through persistently activated and GABAB receptor-controlled potassium channels as well as GABAA receptor-controlled chloride channels. PKC also depresses persistent potassium currents but it potentiates excitatory and inhibitory synaptic currents. The clinical significance of these intracellular signal pathways is demonstrated in a case of a child suffering from apneustic breathing, who was successfully treated with a 5HT-1A receptor agonist.

Animals↗
PubMed2003

von Willebrand factor (VWF)-dependent human platelet activation: porcine VWF utilizes different transmembrane signaling pathways than does thrombin to activate platelets, but both require protein phosphatase function.

The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. To determine if VWF-dependent platelet activation requires the participation of pivotal transmembrane signaling pathways, we analyzed VWF-dependent platelet activation profiles following inhibition of several transmembrane signaling intermediates. This was accomplished using porcine VWF, which has been shown to interact with human GPIb independently of shear stress or ristocetin. Platelet alpha (CD62) and lysozomal granule release (CD63), microparticle formation, and platelet agglutination/aggregation were evaluated. The ability of signaling inhibitors to prevent VWF-dependent platelet activation was compared to their ability to inhibit thrombin-dependent activation. The results demonstrate that VWF-dependent platelet activation can occur independently of the activities of protein kinase C (PKC), wortmannin-sensitive phosphatidylinositide 3-kinase, and phospholipase C, as well as independently of elevations in the concentration of intracellular calcium. In sharp contrast, these transmembrane signaling intermediates are required for thrombin-dependent platelet activation. In addition, thrombin-dependent but not VWF-dependent platelet activation was associated with elevations in the concentration of intracellular calcium under the conditions used. The family of signaling intermediates which appeared to be pivotal for both thrombin- and VWF-dependent platelet activation were the protein tyrosine phosphatases and the serine/threonine phosphatases. It is concluded that thrombin-dependent platelet activation relies on the activation of several transmembrane signaling pathways, whereas VWF-dependent platelet activation is dependent upon the activity of protein phosphatases. Inhibition of these phosphatases in vivo may provide a novel therapeutic approach for treating VWF-dependent platelet disorders such as thrombotic thrombocytopenic purpura or arterial thrombosis.

Adenosine Diphosphate↗
PubMed2002

Vascular signaling pathways in the metabolic syndrome.

There are several potential cellular and molecular pathways whereby cardiovascular risk factors act through very specific signal transduction pathways in the formation of atherosclerosis, as seen often in the metabolic syndrome. Many examples point to multiple postreceptor defects in the insulin signaling pathway in vascular tissue, however, there are differences in the insulin receptor pathway in vascular tissue compared with skeletal muscle or fat. In addition to insulin receptors, insulin may affect atherosclerotic changes in the vascular cells via stimulation of insulin-like growth factor-1 receptors and their signaling pathway. Insulin also causes activation of the vascular renin-angiotensin system in both vascular smooth muscle cells and endothelial cells. Insulin-activated tissue renin-angiotensin system leads to increased cell growth and contributes to the cause of atherosclerosis. The fact that agents that inhibit the renin-angiotensin system also block insulin-mediated renin-angiotensin system expression and cell growth reinforces the potential implication of a vascular insulin-renin-angiotensin system pathway. Finally, novel substances such as the adipokines, factors produced from fat cells, reveal new risk factors in the metabolic syndrome and offer further evidence for a link between insulin resistance and accelerated atherosclerosis.

Animals↗
PubMed2005

Dioscorin isolated from Dioscorea alata activates TLR4-signaling pathways and induces cytokine expression in macrophages.

The Toll-like receptor 4 (TLR4)-signaling pathway is crucial for activating both innate and adaptive immunity. TLR4 is a promising molecular target for immune-modulating drugs, and TLR4 agonists are of therapeutic potential for treating immune diseases and cancers. Several medicinal herb-derived components have recently been reported to act via TLR4-dependent pathways, suggesting that medicinal plants are potential resources for identifying TLR4 activators. We have applied a screening procedure to systematically identify herbal constituents that activate TLR4. To exclude possible LPS contamination in these plant-derived components, a LPS inhibitor, polymyxin B, was added during screening. One of the plant components we identified from the screening was dioscorin, the glycoprotein isolated from Dioscorea alata. It induced TLR4-downstream cytokine expression in bone marrow cells isolated from TLR4-functional C3H/HeN mice but not from TLR4-defective C3H/HeJ mice. Dioscorin also stimulated multiple signaling molecules (NF-kappaB, ERK, JNK, and p38) and induced the expression of cytokines (TNF-alpha, IL-1beta, and IL-6) in murine RAW 264.7 macrophages. Furthermore, the ERK, p38, JNK, and NF-kappaB-mediated pathways are all involved in dioscorin-mediated TNF-alpha production. In summary, our results demonstrate that dioscorin is a novel TLR4 activator and induces macrophage activation via typical TLR4-signaling pathways.

Animals↗
PubMed2002

The serine protease plasmin triggers expression of MCP-1 and CD40 in human primary monocytes via activation of p38 MAPK and janus kinase (JAK)/STAT signaling pathways.

The mechanism of proinflammatory activation of human monocytes by plasmin is unknown. Here we demonstrate that in human primary monocytes, plasmin stimulates mitogen-activated protein kinase (MAPK) signaling via phosphorylation of MAPK kinase 3/6 (MKK3/6) and p38 MAPK that triggers subsequent DNA binding of transcription factor activator protein-1 (AP-1). The AP-1 complex contained phosphorylated c-Jun and ATF2, and its DNA binding activity was blocked by the p38 MAPK inhibitor SB203580. In addition, plasmin elicits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, as detected by phosphorylation of JAK1 tyrosine kinase and STAT1 and STAT3 proteins. Plasmin-induced DNA binding of STAT1 and STAT3 was blocked by SB203580 and AG490, inhibitors of p38 MAPK and JAK, respectively, but not by U0126, an inhibitor of MKK1/2. DNA binding of NF-kappaB remained unaffected by any of these inhibitors. The plasmin-induced signaling led to expression of monocyte chemoattractant protein-1 (MCP-1) and CD40, which required activation of both p38 MAPK and JAK/STAT signaling pathways. Additionally, signaling through both p38 MAPK and JAK is involved in the plasmin-mediated monocyte migration, whereas the formylmethionylleucylphenylalanine-induced chemotaxis remained unaffected. Taken together, our data demonstrate a novel function of the serine protease plasmin in a proinflammatory signaling network.

Blotting, Western↗
PubMed1997

Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways.

The interferon-inducible double-stranded RNA protein kinase PKR controls protein synthesis through the phosphorylation of eukaryotic translation initiation factor (eIF)-2. In addition to its demonstrated role in translational control, several reports have suggested a transcriptional role for PKR. Here we report that PKR is involved in IFN- and dsRNA-signaling pathways by modulating the function of the signal transducer and activator of transcription STAT1. We also show that PKR associates with STAT1 in mouse and human cells. The association is not a kinase-substrate interaction since STAT1 phosphorylation is not modified by PKR in vitro or in vivo. In addition, the formation of the PKR-STAT1 complex is not dependent upon the enzymatic activity of PKR but does require the dsRNA-binding domain of PKR. Moreover, there is a concomitant decrease in PKR-STAT1 interaction and increase in STAT1 DNA binding in response to IFNs or dsRNA. These findings suggest that PKR plays an important role in IFN and dsRNA-signaling pathways by modulating the transcriptional function of STAT1.

3T3 Cells↗
PubMed2001

A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase.

Stimulation of phosphoinositide-hydrolysing phospholipase C (PLC) generating inositol-1,4,5-trisphosphate is a major calcium signalling pathway used by a wide variety of membrane receptors, activating distinct PLC-beta or PLC-gamma isoforms. Here we report a new PLC and calcium signalling pathway that is triggered by cyclic AMP (cAMP) and mediated by a small GTPase of the Rap family. Activation of the adenylyl cyclase-coupled beta2-adrenoceptor expressed in HEK-293 cells or the endogenous receptor for prostaglandin E1 in N1E-115 neuroblastoma cells induced calcium mobilization and PLC stimulation, seemingly caused by cAMP formation, but was independent of protein kinase A (PKA). We provide evidence that these receptor responses are mediated by a Rap GTPase, specifically Rap2B, activated by a guanine-nucleotide-exchange factor (Epac) regulated by cAMP, and involve the recently identified PLC-epsilon isoform.

Adenylyl Cyclases↗
PubMed2003

Intrinsic activation of PI3K/Akt signaling pathway and its neuroprotective effect against retinal injury.

PURPOSE: The aim of this study was to determine whether the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway can function as a neuroprotective pathway following induced retinal injury. METHODS: The activation of Akt was assessed by immunoblot analysis, and the role of PI3K/Akt pathway was evaluated by TUNEL staining and counting the number of retrogradely-labeled retinal ganglion cells (RGCs) in the whole retina at 168 h after injury with or without PI3K specific inhibitor, LY294002. RESULTS: Akt was induced within one hr and reached a maximum 6 hrs after optic nerve clamping. The activation was observed in the RGC layer including RGCs, the inner plexiform layer, inner nuclear layer, and in the photoreceptor outer segments. The number of surviving RGCs was decreased significantly 168 hrs after injury. LY294002 partially inhibited the activation of Akt, and significantly decreased the number of surviving RGCs as compared with that of injury alone. CONCLUSIONS: These results indicate that the PI3K/Akt signaling pathway is activated intrinsically and has a neuroprotective effect on injured RGCs.

Animals↗