The involvement of phosphatidylinositol 3-kinase /Akt signaling in high glucose-induced downregulation of GLUT-1 expression in ARPE cells

Kim, Dong-Il; Lim, Sul-Ki; Park, Min-Jung; Han, Ho Jae; Kim, Gye-Yeop; Park, Soo Hyun

doi:10.1016/j.lfs.2006.10.026

Cited by 54 publications

(41 citation statements)

References 32 publications

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“…In endothelial and retinal pigment epithelial cells exposed to HG, involvement of PKC in the long-term (24 h) phosphorylation of Akt at S473 was suggested by blockade with a general PKC inhibitor. 9,33 Our study explores the role of PKC as potential glucose-induced S473 kinases in MCs. This report extends the current understanding of the pathogenesis of diabetic glomerular disease in (1) identifying PKC-␤1 as an Akt S473 kinase in response to HG in MCs and demonstrating relevance in vivo in diabetic kidneys, (2) showing that PKC-␤1/Akt interaction is required for TGF-␤ upregulation, and (3) identifying EGFR transactivation as an upstream mediator of this signaling cascade.…”

Section: Discussionmentioning

confidence: 99%

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Peng²,

Zhang³

et al. 2009

Journal of the American Society of Nephrology

102

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Accumulation of glomerular matrix is a hallmark of diabetic nephropathy. The serine/threonine kinase Akt mediates glucose-induced upregulation of collagen I in mesangial cells through transactivation of the EGF receptor (EGFR). In addition, in renal tubular cells, glucose-induced secretion of TGF-␤ requires phosphoinositide-3-OH kinase, suggesting a possible role for Akt in the modulation of TGF-␤ expression, but the mechanisms of Akt activation and its involvement in TGF-␤ regulation are unknown. Here, in primary mesangial cells, high glucose induced AktS473 phosphorylation, which correlates with its activation, in a protein kinase C ␤ (PKC-␤)-dependent manner. Glucose led to PKC-␤1 membrane translocation and association with Akt, and PKC-␤1 immunoprecipitated from glucose-treated cells phosphorylated recombinant Akt on S473. PKC is known to mediate glucose-induced TGF-␤1 upregulation through the transcription factor AP-1; here, inhibitors of phosphoinositide-3-OH kinase, PKC-␤ and Akt, and dominant-negative Akt all prevented glucose-induced activation of AP-1 and upregulation of TGF-␤1. Finally, pharmacologic and dominant negative inhibition of EGFR blocked glucose-induced activation of PKC-␤1, phosphorylation of AktS473, activation of AP-1, and upregulation of TGF-␤1. In vivo, the PKC-␤ inhibitor ruboxistaurin prevented Akt activation in the renal cortex of diabetic rats. In conclusion, PKC-␤1 is an Akt S473 kinase in glucose-treated mesangial cells, and TGF-␤1 transcriptional upregulation requires EGFR/PKC-␤1/Akt signaling. New therapeutic approaches for diabetic nephropathy may result from targeting components of this pathway, particularly the initial EGFR transactivation. 20: 554 -566, 200920: 554 -566, . doi: 10.1681 The kidney is an important site of diabetic microvascular complications, and hyperglycemia is central to glomerular matrix accumulation. Although strict glucose control and inhibition of the reninangiotensin system are effective in delaying the development of nephropathy, disease progression often occurs. The development of new treatment approaches is thus an important goal. J Am Soc NephrolWe have shown that collagen I induction by high glucose (HG) requires activation of the serine/threonine kinase Akt, and this depends on transactivation of the EGF receptor (EGFR). 1 Akt activation requires membrane translocation and phosphorylation on two sites, S473 and T308. 2 Phosphoinositide-3-OH kinase (PI3K) is an upstream mediator of Akt activation, generating phosphorylated lipid second messengers that recruit proteins with pleckstrin homology domains such as Akt to the membrane. 3 At the membrane, phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates Akt at T308. 3 Several S473 kinases, however, have

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Section: Discussionmentioning

confidence: 99%

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Peng²,

Zhang³

et al. 2009

Journal of the American Society of Nephrology

102

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“…The activation of PKC is involved in retinal and choroidal neovascularization in RPE cells (Bian et al, 2007). In our previous report, although we suggested that PKC was responsible for the downregulation of glucose transporter-1 (GLUT-1) in ARPE cells (Kim et al, 2007), we did not examine the role of PKC in the regulation of glutamate uptake. These findings suggest that diverse molecules such as COX, Akt, and PKC are involved in the BK-induced alteration of glutamate uptake in ARPE cells, but the involvement of COX, Akt, and PKC signaling in glutamate uptake in RPE cells is unclear.…”

Section: Introductionmentioning

confidence: 90%

Bradykinin stimulates glutamate uptake via both B1R and B2R activation in a human retinal pigment epithelial cells

et al. 2008

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“…Metabolic changes associated with diabetes mellitus cause vascular leakage and a subsequent alteration of the phenotype of RPE cells, resulting in changes in cell function (Stevens et al, 1999). In our previous report (Kim et al, 2007), we showed that high glucose impairs the function of human retinal pigment epithelium (ARPE) cells.…”

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confidence: 95%

Both B1R and B2R act as intermediate signaling molecules in high glucose‐induced stimulation of glutamate uptake in ARPE cells

Lim

Han

Kim

et al. 2009

Journal Cellular Physiology

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Bradykinin (BK) is a potent modulator of biological processes in the retina, and retinal pigment epithelial cells (RPE) and the regulation of glutamate are believed to be important in the pathogenesis of diabetic retinopathy. However, the mechanism by which BK regulates glutamate uptake in RPE cells in diabetic retinopathy is unknown. Here, we examined the involvement of BK receptors in high glucose-induced dysfunction of glutamate uptake in human ARPE cells. High glucose stimulated glutamate uptake and the expression of excitatory amino acid transporter-4 (EAAT4) mRNA, and these were blocked by treatment with small interfering RNA (siRNA) for BK1 receptor (B1R) and BK2 receptor (B2R), but not scrambled siRNA, supporting an involvement of B1R and B2R in this process. High glucose-stimulated glutamate uptake was also blocked by the B1R antagonist [des-Arg(10)]-HOE 140 and the B2R antagonist HOE 140. High glucose increased B1R and B2R mRNA and protein expression in a time-dependent manner, increased B1R and B2R translocation from the cytosol to the nucleus, and stimulated kininogen, kallikrein, and kininase I mRNA expression. We examined whether BK receptors were involved in high glucose-induced signaling pathways. High glucose stimulated arachidonic acid release, cytosolic phospholipase A(2) and cyclooxygenase-2 proteins, nuclear factor-kappaB activation, and inhibitor-kappaB activation; these events were blocked by treatment with B1R and B2R siRNAs, but not scrambled siRNA. In addition, high glucose-induced stimulation of glutamate uptake was blocked by the cyclooxygenase-2 inhibitors arachidonyl trifluoromethyl ketone, mepacrine, 5-bromo-2-(4-fluorophenyl)-3-[4-(methyl-sulfonyl)phenyl]-thiophene, and N-[2-cyclohexyloxy-4-nitrophenyl] methane-sulfonamide, and by the nuclear factor-kappaB inhibitors pyrrolidine dithiocarbamate and SN-50.

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The involvement of phosphatidylinositol 3-kinase /Akt signaling in high glucose-induced downregulation of GLUT-1 expression in ARPE cells

Cited by 54 publications

References 32 publications

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells

Bradykinin stimulates glutamate uptake via both B1R and B2R activation in a human retinal pigment epithelial cells

Both B1R and B2R act as intermediate signaling molecules in high glucose‐induced stimulation of glutamate uptake in ARPE cells

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