12-Lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy

Kang, Shin Wook; Adler, Sharon G.; Nast, Cynthia C.; LaPage, Janine; Gu, Jia; Nadler, Jerry L.; Natarajan, Rama

doi:10.1046/j.1523-1755.2001.0590041354.x

Cited by 100 publications

(128 citation statements)

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“…Its biological effects have been studied in several cell types [25,[40][41][42]. The physiological function of low basal levels of 12LO products in the islets remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

et al. 2005

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Aims/hypothesis: Beta cell inflammation and cytokine-induced toxicity are central to autoimmune diabetes development. Lipid mediators generated upon lipoxygenase (LO) activation can participate in inflammatory pathways. 12LO-deficient mice are resistant to streptozotocin-induced diabetes. This study sought to characterise the cellular processes involving 12LO-activation lipid inflammatory mediator production in cytokine-treated pancreatic beta cells. Methods: Islets and beta cell lines were treated with a combination of IL-1β, IFN-γ and TNF-α, or the 12LO product 12(S)-hydroxyeicosatetraenoic acid (HETE). Insulin secretion was measured using an enzyme immunoassay, and cell viability was evaluated using an in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay. 12LO activity was evaluated and 12LO protein levels were determined using immunoblotting with a selective leucocyte type 12LO antibody. Cellular localisation of 12LO was evaluated using immunocytochemistry. Results: Basal expression of leucocyte type 12LO protein was found in human and mouse islets and in several rodent beta cell lines. In mouse β-TC3 cells, and in human islets, cytokines induced release of 12-HETE within 30 min. Cytokine addition also induced a rapid translocation of 12LO protein from the cytosol to the nucleus of β-TC3 cells as shown by subcellular fractionation and immunostaining. Cytokine-induced cell death and inhibition of insulin secretion were partially reversed by baicalein, a 12LO inhibitor. 12(S)-HETE inhibited β-TC3 cell insulin release in a time-and concentration-dependent manner. Incubating β-TC3 cells with 100 nmol/l of 12(S)-HETE resulted in a 57% reduction in basal insulin release (6 h), and a 17% increase in cell death (18 h) as compared with untreated cells. 12(S)-HETE activated the stress-activated protein kinase c-Jun N-terminal kinase and p38 within 15 min, as judged by increased kinase protein phosphorylation. Conclusions/interpretation: The data suggest that inflammatory cytokines rapidly activate 12LO and show for the first time that cytokines induce 12LO translocation. The effects of 12-HETE on insulin secretion, cytotoxicity and kinase activation were similar to the effects seen with cytokines. The results provide mechanistic information of cytokine-induced toxic effects on pancreatic beta cells and support the hypothesis that blocking 12LO activation could provide a new therapeutic way to protect pancreatic beta cells from autoimmune injury.

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“…Its biological effects have been studied in several cell types [25,[40][41][42]. The physiological function of low basal levels of 12LO products in the islets remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

et al. 2005

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“…The deleterious effects of hyperglycemia are characteristically observed in cells and tissues that do not depend on insulin for glucose entry, and, hence, are not capable of down-regulating the HG-signaling pathway, as in neuronal, retinal, and renal cells (23). Regarding the MC response to the HG ambience, a number of studies have investigated various signaling pathways in glomerular MCs that are affected in response to HG (24)(25)(26)(27). This study indicates that a Rho͞p21-dependent signaling pathway is involved in the HG-induced proliferation of MCs, which is seen in the early stages of diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy

Danesh

Sadeghi

Amro

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

222

174

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“…Although 12/15-lipoxygenase apparently does not play a key role in the degeneration of retinal capillaries in early diabetic retinopathy, other investigations implicate 12/15-lipoxygenase in the pathogenesis of diabetes-induced macrovascular endothelial cell dysfunction and atherosclerosis, as well as microvascular complications such as nephropathy and peripheral neuropathy (28,48,49). These observations underscore that the pathogenesis of diabetes-related complications is likely tissue specific.…”

Section: Diabetes Vol 57 May 2008mentioning

confidence: 96%

5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy

et al. 2008

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OBJECTIVE-Lipoxygenases are regulators of chronic inflamation and oxidative stress generation. We evaluated the role of 5-and 12-lipoxygenases in the development of diabetic retinopathy.RESEARCH DESIGN AND METHODS-Wild-type mice, 5-lipoxygenase-deficient mice, and 12/15-lipoxygenase-deficient mice were assessed 1) after 9 months of diabetes for retinal histopathology and leukotriene receptor expression and 2) after 3 months of diabetes for leukostasis and retinal superoxide generation.RESULTS-Diabetic wild-type mice developed the expected degeneration of retinal capillaries and pericytes and increases in both leukostasis and superoxide production (P Ͻ 0.006). We found no evidence of diabetes-induced degeneration of retinal ganglion cells in these animals. The vascular histopathology was significantly inhibited in 5-lipoxygenase-deficient mice, but not in 12/15-lipoxygenase-deficient mice. Retinas from diabetic 5-lipoxygenase-deficient mice also had significantly less leukostasis, superoxide production, and nuclear factor-B (NF-B) expression (all P Ͻ 0.006), whereas retinas from diabetic 12/15-lipoxygenase-deficient mice had significantly less leukostasis (P Ͻ 0.005) but not superoxide production or NF-B expression. Retinas from diabetic wild-type mice were enriched with receptors for the 5-lipoxygenase metabolite leukotriene B 4 . Diabetesinduced histological and biochemical alterations were significantly reduced in 5-lipoxygenase-deficient mice, but not 12/15-lipoxygenase-deficient mice. M any recent studies support the hypothesis that inflammatory insults to the retina play an important role in development of the early stages of diabetic retinopathy (1-4). A hallmark lesion of this early retinopathy is degeneration of retinal capillaries (5-7). This capillary degeneration is believed to be important because when the capillary degeneration is extensive enough, the retina is believed to become ischemic, ultimately leading to retinal neovascularization. The inflammatory response in early diabetic retinopathy includes diabetes-induced increases in 1) cytokine activation, 2) leukostasis, 3) vascular permeability, and 4) nuclear factor-B (NF-B)-regulated expression of proinflammatory molecules, including inducible NO (nitric oxide) synthase, cyclooxygenase-2, and intracellular adhesion molecule-1 (ICAM-1) (4,8 -13). The inflammation might damage retinal capillaries through the generation of reactive oxygen species, occlusion of vessels by leukostasis, promotion of retinal vascular leakage, and induction of endothelial cell death (1,14 -16). CONCLUSIONS-5-LipoxygenasePrior studies have elucidated that metabolites of arachidonic acid, collectively known as the eicosanoids, are critical in the pathogenesis of chronic inflammatory states such as in asthma, arthritis, and colitis (17-19). 5-Lipoxygenase metabolites of arachidonic acid, the leukotrienes, play a role in these inflammatory processes. Generation of leukotrienes starts with the release of arachidonic acid from phospholipids by cPLA 2 (cytosolic phospholipase ...

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12-Lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy

Abstract: In MCs exposed to HG and in diabetic rat glomeruli, increments in 12-LO mRNA and protein are associated with changes modeling diabetic nephropathy. These findings suggest a role for the 12-LO pathway in the pathogenesis of diabetic nephropathy.

Cited by 100 publications

References 39 publications

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy

5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy

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