BACKGROUND: An interaction of insulin with angiotensin II effects could be pathophysiologically important for the pathogenesis of atherosclerosis and hypertension. METHODS AND RESULTS: We examined the effect of insulin on AT1 receptor gene expression in cultured vascular smooth muscle cells (VSMCs). A 24-hour incubation with insulin (100 nmol/L) produced a 2-fold increase in AT1 receptor density on VSMCs, as assessed by radioligand binding assays. This enhanced AT1 receptor expression was caused by a time- and concentration-dependent upregulation of the AT1 receptor mRNA levels, as assessed by Northern analysis. The maximal effect was detected after a 24-hour incubation of cells with 100 nmol/L insulin (270+/-20%). AT1 receptor upregulation was caused by a stabilization of the AT1 receptor mRNA, because the AT1 receptor mRNA half-life was prolonged from 5 hours under basal conditions to 10 hours after insulin stimulation. In contrast, insulin had no influence on AT1 receptor gene transcription, as assessed by nuclear run-on assays. The insulin-induced AT1 receptor upregulation was followed by an increased functional response, because angiotensin II evoked a significantly elevated intracellular release of calcium in cells that were preincubated with 100 nmol/L insulin for 24 hours. The insulin-induced AT1 receptor upregulation was dependent on tyrosine kinases, as assessed by experiments with the tyrosine kinase inhibitor genistein. Furthermore, experiments using the intracellular calcium chelator bis(2-amino-5-methylphenoxy)ethane-N, N,N',N'-tetraacetic acid tetraacetoxymethyl ester suggest that intracellular calcium release may be involved in AT1 receptor regulation. CONCLUSIONS: Insulin-induced upregulation of the AT1 receptor by posttranscriptional mechanisms may explain the association of hyperinsulinemia with hypertension and arteriosclerosis, because activation of the AT1 receptor plays a key role in the regulation of blood pressure and fluid homeostasis.
BACKGROUND: An interaction of insulin with angiotensin II effects could be pathophysiologically important for the pathogenesis of atherosclerosis and hypertension. METHODS AND RESULTS: We examined the effect of insulin on AT1 receptor gene expression in cultured vascular smooth muscle cells (VSMCs). A 24-hour incubation with insulin (100 nmol/L) produced a 2-fold increase in AT1 receptor density on VSMCs, as assessed by radioligand binding assays. This enhanced AT1 receptor expression was caused by a time- and concentration-dependent upregulation of the AT1 receptor mRNA levels, as assessed by Northern analysis. The maximal effect was detected after a 24-hour incubation of cells with 100 nmol/L insulin (270+/-20%). AT1 receptor upregulation was caused by a stabilization of the AT1 receptor mRNA, because the AT1 receptor mRNA half-life was prolonged from 5 hours under basal conditions to 10 hours after insulin stimulation. In contrast, insulin had no influence on AT1 receptor gene transcription, as assessed by nuclear run-on assays. The insulin-induced AT1 receptor upregulation was followed by an increased functional response, because angiotensin II evoked a significantly elevated intracellular release of calcium in cells that were preincubated with 100 nmol/L insulin for 24 hours. The insulin-induced AT1 receptor upregulation was dependent on tyrosine kinases, as assessed by experiments with the tyrosine kinase inhibitor genistein. Furthermore, experiments using the intracellular calcium chelator bis(2-amino-5-methylphenoxy)ethane-N, N,N',N'-tetraacetic acid tetraacetoxymethyl ester suggest that intracellular calcium release may be involved in AT1 receptor regulation. CONCLUSIONS:Insulin-induced upregulation of the AT1 receptor by posttranscriptional mechanisms may explain the association of hyperinsulinemia with hypertension and arteriosclerosis, because activation of the AT1 receptor plays a key role in the regulation of blood pressure and fluid homeostasis.
Authors: Marina C Muñoz; Valeria Burghi; Johanna G Miquet; Jorge F Giani; Ricardo D Banegas; Jorge E Toblli; Yimin Fang; Feiya Wang; Andrzej Bartke; Fernando P Dominici Journal: J Endocrinol Date: 2014-04-22 Impact factor: 4.286
Authors: Hannes Reuter; Sabine Grönke; Christian Adam; Maida Ribati; Jan Brabender; Carsten Zobel; Konrad F Frank; Jens Wippermann; Robert H G Schwinger; Klara Brixius; Jochen Müller-Ehmsen Journal: Mol Cell Biochem Date: 2007-10-20 Impact factor: 3.396
Authors: Michael Backlund; Kirsi Paukku; Laurent Daviet; Rudolf A De Boer; Erkka Valo; Sampsa Hautaniemi; Nisse Kalkkinen; Afshin Ehsan; Kimmo K Kontula; Jukka Y A Lehtonen Journal: Nucleic Acids Res Date: 2009-02-26 Impact factor: 16.971