Decreased binding of epidermal growth factor in placentas from streptozotocin-diabetic rats.

Sissom, Janice F.; Stenzel, W.; Warshaw, Joseph B.

doi:10.1172/jci113054

Cited by 21 publications

(20 citation statements)

References 23 publications

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“…In diabetes, glycation of proteins is associated with increased generation of GO and MGO (3,38) and altered EGFR signaling (14 -17). Concurrent to the AGE/RAGEinduced cell activation (39), this GO/MGO-induced impairment in response of growth factors and the subsequent trophic deprivation may be implicated in the pathophysiology of chronic diabetic complications, such as microvascular disease (including neuropathy, nephropathy, and retinopathy) and macrovascular disease (and associated accelerated atherosclerosis), impaired wound healing (33,40), and placenta dysfunction (16).…”

Section: Discussionmentioning

confidence: 99%

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Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

et al. 2002

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Formation of advanced glycation end products (AGEs)is considered a potential link between hyperglycemia and chronic diabetic complications, including disturbances in cell signaling. It was hypothesized that AGEs alter cell signaling by interfering with growth factor receptors. Therefore, we studied the effects of two AGE precursors, glyoxal (GO) and methylglyoxal (MGO), on the epidermal growth factor receptor (EGFR) signaling pathway in cultured cells. Both compounds prevented tyrosine autophosphorylation induced by epidermal growth factor (EGF) in a time-and dose-dependent manner as well as phospholipase C␥1 recruitment and subsequent activation of extracellular signal-regulated kinases. AGE precursors inhibit EGF-induced EGFR autophosphorylation and tyrosine kinase activity in cell membranes and in EGFR immunoprecipitates. In addition, AGE precursors strongly inhibited cellular phosphotyrosine phosphatase activities and residual EGFR dephosphorylation. AGE precursors induced the formation of EGFR cross-links, as shown by the cross-reactivity of modified EGFR with an anti-N ⑀ (carboxymethyl) lysine antibody, suggesting that altered EGFR signaling was related to carbonyl-amine reactions on EGFR. Aminoguanidine, an inhibitor of AGE formation, partially prevented the EGFR dysfunction induced by GO and MGO. These data introduce a novel mechanism for impaired cellular homeostasis in situations that lead to increased production of these reactive aldehydes, such as diabetes. Diabetes 51:1535-1542, 2002 T he Maillard reaction comprises the nonenzymatic reaction of reducing sugars with molecules containing an amino group, including proteins, phospholipids, and DNA (1,2). After the reversible formation of a Schiff's base between the reducing sugar and free amino group, this reaction proceeds to form advanced glycation end products (AGEs). Aldehydes such as glyoxal (GO) and methylglyoxal (MGO) are also able to induce AGE formation (3). GO and MGO can be generated during glycation of proteins by glucose (3); during lipid peroxidation (4); from metabolic processes, such as base-catalyzed phosphate elimination of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate; and also during the metabolism of acetone and threonine (5).During chronic complications of diabetes and aging, the levels of AGEs derived from the reaction of GO and MGO with proteins rise in plasma proteins, extracellular matrix, and lens proteins (6 -8). Modification of proteins through derivatization by GO and MGO may induce interaction with specific receptors, such as the RAGE and AGE-R family (9), or directly alter protein functions. For instance, MGO inhibits mitochondrial respiration, membrane ATPases and glyceraldehyde-3-phosphate dehydrogenases (10), and DNA and protein synthesis, thereby inducing growth arrest and cell death (11).Because altered response to growth factor may be implicated in the pathogenesis of diabetic ulcers (12) and vascular diseases associated with diabetes (13), we hypothesized that GO and MGO may modify growth factor recepto...

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Section: Discussionmentioning

confidence: 99%

“…Our investigations were mainly focused on the epidermal growth factor receptor (EGFR) because high glucose concentrations lead to abnormal epidermal growth factor (EGF) signaling (14) and diabetes reduces EGFR autophosphorylation (15)(16)(17).…”

mentioning

confidence: 99%

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

et al. 2002

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“…Decreases in liver membrane EGF binding have also been noted in fa/fa Zucker rats, another animal model of hyperinsulinemic obesity. In our own laboratory, EGF binding and receptor phosphorylation was observed to be reduced in liver membranes from streptozotocin-treated diabetic rats (39). In pregnant, streptozotocin-treated diabetic rats, there was a 30% reduction in numbers of EGF receptors in placental membranes and a twofold elevation in circulating fetal EGF levels.…”

Section: Methodsmentioning

confidence: 85%

Epidermal growth factor receptor defects in leprechaunism. A multiple growth factor-resistant syndrome.

Reddy¹,

Kahn²

1989

J. Clin. Invest.

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“…Placentas were removed and weighed immediately after animals were killed. The membrane fraction was prepared by a modification of the method of Morishige et al (4,9). Tissue was homogenized in a polytron homogenizer in 10 vol of 0.3 M sucrose in 25 mM Tris-HCI, pH 7.6, containing 10 mM MgCI2.…”

Section: Animal Model Pregnant Adult Female Sprague-dawley Ratsmentioning

confidence: 99%

“…The amount of EGF-like activity in amniotic fluid and fetal serum was measuredby radioreceptor assay. Human placental membranes were isolated according to a modification of the method of Hock and Hollenberg (4,12) and suspended at a concentration of 5-pg membrane protein per tube. The assay mixture contained 30,000 to 40,000 dpm I2jI-EGF, varying amounts of cold receptor grade EGF (0-1000 ng/ tube), or test sample in a final vol of 300 p1.…”

Section: Animal Model Pregnant Adult Female Sprague-dawley Ratsmentioning

confidence: 99%

Increased Binding of Epidermal Growth Factor to Placental Membranes of Intrauterine Growth Restricted Fetal Rats

1989

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To examine the relationship between nutrient supply and fetal and placental growth, we examined epidermal growth factor (EGF) binding to membranes prepared from placentas of growthrestricted fetal rats. Intrauterine growth retardation was accomplished by unilateral ligation of the uterine artery; fetal rats on the contralateral uterine horn served as controls. Fetal growth restriction was accompanied by decreased placental wt at 19 and 20 days' gestation and significantly decreased placental glycogen content at 20 and 21 days, 30% and 15%, respectively. Placental DNA content and protein/DNA ratios were similar in the growthrestricted and control groups. Fetal growth and maturation is determined primarily by the fetal genome but can be influenced by a number of important genetic, environmental, and maternal factors. These include a variety of congenital malformations and chromosomal disorders, environmental toxins such as cigarette smoke and alcohol, and maternal medical conditions which can restrict nutrient supply to the fetus. Fetuses with decreased uteroplacental blood flow may exhibit to varying degrees, depending on the severity of substrate and oxygen restrictions, low birth wt with sparing of brain growth, polycythemia, hypoglycemia secondary to defective glucose homeostasis, and accelerated lung maturation. The biologic mechanisms underlying the alterations in growth seen with decreased nutrient supply are poorly understood. In previous work (1-4), we reported that placentomegaly and maturational delay in fetuses of diabetics was associated with a striking decrease in the binding of epidermal growth factor to membranes prepared from the diabetic placentas. In light of these observations and because of the role of EGF in cellular proliferation and Supported by NIH Grant HL30119-07.organ differentiation in numerous cell types and animal species (5-7), we examined EGF binding to membranes prepared from placentas of fetal rats with growth restriction secondary to uterine artery ligation. In these studies, we raise the possibility that EGF binding to placental membranes is regulated by substrate flux and is associated with maturational changes in diabetic and IUGR fetuses. MATERIALS AND METHODS Animal model. Pregnant adult female Sprague-Dawley ratswere obtained from Holtzmann Lab Animals (Madison, WI) at 7-9 days' gestation (the morning that sperm were detected was designated as day 0 of pregnancy). Females were maintained on a 121 12 h lightldark cycle at 24'2, and given food and tap water ad libitum for 7-9 days before animal surgery. On days 16, 17, or 18 of gestation, unilateral uterine artery ligation was performed by a modification of the method of Wigglesworth (8) under Metofane (Pitman-Moore, Washington Crossing, NJ) inhalation anesthesia as follows. A midline incision of the lower abdomen was made, and the uterine horns were exteriorized and inspected. A single 3.0 silk ligature was placed securely around the main branch of the uterine artery close to the cervix. Only horns containing six or more fe...

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Decreased binding of epidermal growth factor in placentas from streptozotocin-diabetic rats.

Cited by 21 publications

References 23 publications

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

Advanced Glycation End Product Precursors Impair Epidermal Growth Factor Receptor Signaling

Epidermal growth factor receptor defects in leprechaunism. A multiple growth factor-resistant syndrome.

Increased Binding of Epidermal Growth Factor to Placental Membranes of Intrauterine Growth Restricted Fetal Rats

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