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Marina C Muñoz Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Cátedra de Farmacología, Laboratorio de Medicina Experimental, IQUIFIB

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Jorge F Giani Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Cátedra de Farmacología, Laboratorio de Medicina Experimental, IQUIFIB

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Marcos A Mayer Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Cátedra de Farmacología, Laboratorio de Medicina Experimental, IQUIFIB

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Jorge E Toblli Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Cátedra de Farmacología, Laboratorio de Medicina Experimental, IQUIFIB

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Daniel Turyn Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Cátedra de Farmacología, Laboratorio de Medicina Experimental, IQUIFIB

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Fernando P Dominici Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Cátedra de Farmacología, Laboratorio de Medicina Experimental, IQUIFIB

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The IκB kinase-β (IKK-β)/nuclear factor-κB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3β. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

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Lorena González
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Ma. Eugenia Díaz
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Johanna G Miquet
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Ana I Sotelo
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Diego Fernández Departamento de Química Biológica, Cátedra de Bioquímica Humana, Geriatrics Research, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina

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Fernando P Dominici
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Andrzej Bartke Departamento de Química Biológica, Cátedra de Bioquímica Humana, Geriatrics Research, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina

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Daniel Turyn
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Epidermal growth factor (EGF) is a key regulator of cell survival and proliferation involved in the pathogenesis and progression of different types of cancer. The EGF receptor (EGFR) is activated by binding of the specific ligand but also by transactivation triggered by different growth factors including GH. Chronically, elevated GH levels have been associated with the progression of hepatocellular carcinoma. Considering EGF and GH involvement in cell proliferation and their signaling crosstalk, the objective of the present study was to analyze GH modulatory effects on EGF signaling in liver. For this purpose, GH receptor-knockout (GHR-KO) and GH-overexpressing transgenic mice were used. EGFR content was significantly decreased in GHR-KO mice. Consequently, EGF-induced phosphorylation of EGFR, AKT, ERK1/2, STAT3, and STAT5 was significantly decreased in these mice. In contrast, EGFR content as well as its basal tyrosine phosphorylation was increased in transgenic mice overexpressing GH. However, EGF stimulation caused similar levels of EGFR, AKT, and ERK1/2 phosphorylation in normal and transgenic mice, while EGF induction of STAT3 and STAT5 phosphorylation was inhibited in the transgenic mice. Desensitization of the STATs was related to decreased association of these proteins to the EGFR and increased association between STAT5 and the tyrosine phosphatase SH2-containing phosphatase-2. While GHR knockout is associated with diminished expression of the EGFR and a concomitant decrease in EGF signaling, GH overexpression results in EGFR overexpression with different effects depending on the signaling pathway analyzed: AKT and ERK1/2 pathways are induced by EGF, while STAT3 and STAT5 activation is heterologously desensitized.

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Lorena González Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Ma Eugenia Díaz Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Johanna G Miquet Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Ana I Sotelo Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Diego Fernández Cátedra de Bioquímica Humana, Facultad de Medicina (UBA), Buenos Aires, Argentina

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Fernando P Dominici Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Andrzej Bartke Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois, USA

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Daniel Turyn Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

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Marina C Muñoz
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Valeria Burghi
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Johanna G Miquet
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Jorge F Giani Departamento de Química Biológica, Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Laboratorio de Medicina Experimental, Department of Internal Medicine, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina

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Ricardo D Banegas
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Jorge E Toblli Departamento de Química Biológica, Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Laboratorio de Medicina Experimental, Department of Internal Medicine, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina

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Yimin Fang Departamento de Química Biológica, Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Laboratorio de Medicina Experimental, Department of Internal Medicine, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina

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Feiya Wang Departamento de Química Biológica, Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Laboratorio de Medicina Experimental, Department of Internal Medicine, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina

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Andrzej Bartke Departamento de Química Biológica, Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Laboratorio de Medicina Experimental, Department of Internal Medicine, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Universidad de Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina

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Fernando P Dominici
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The renin–angiotensin system (RAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease, and chronic renal failure. In this cascade, the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation, and fibrosis, while the ACE2/Ang-(1–7)/Mas receptor axis is protective for end-organ damage. The altered function of the RAS could be a contributing factor to the cardiac and renal alterations induced by GH excess. To further explore this issue, we evaluated the consequences of chronic GH exposure on the in vivo levels of Ang II, Ang-(1–7), ACE, ACE2, and Mas receptor in the heart and the kidney of GH-transgenic mice (bovine GH (bGH) mice). At the age of 7–8 months, female bGH mice displayed increased systolic blood pressure (SBP), a high degree of both cardiac and renal fibrosis, as well as increased levels of markers of tubular and glomerular damage. Angiotensinogen abundance was increased in the liver and the heart of bGH mice, along with a concomitant increase in cardiac Ang II levels. Importantly, the levels of ACE2, Ang-(1–7), and Mas receptor were markedly decreased in both tissues. In addition, Ang-(1–7) administration reduced SBP to control values in GH-transgenic mice, indicating that the ACE2/Ang-(1–7)/Mas axis is involved in GH-mediated hypertension. The data indicate that the altered expression profile of the ACE2/Ang-(1–7)/Mas axis in the heart and the kidney of bGH mice could contribute to the increased incidence of hypertension, cardiovascular, and renal alterations observed in these animals.

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