Transcriptional inhibition of the human insulin receptor gene by aldosterone

Calle, C.; Campión, Javier; Garcı́a-Arencibia, Moisés; Maestro, Beatríz; Dávila, Norma

doi:10.1016/s0960-0760(03)00072-4

Cited by 37 publications

(22 citation statements)

References 41 publications

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“…[37][38][39] The presence of glucocorticoid-responsive elements in the human AT2R has been reported previously. 40 Alternatively, MRs could indirectly modulate AT2R expression, ie, via activation of activating protein-1 (Fos/Jun).…”

Section: Discussionsupporting

confidence: 54%

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

et al. 2005

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Abstract-Recent studies suggested that type 2 angiotensin receptor (AT2R) could contribute to regulation of blood pressure and/or vascular remodeling. A key question relates to the effects of potential modulators of vascular AT2R expression. In the present work, we evaluated if high salt intake (70 mmol/L NaCl in drinking water) could modulate rat mesenteric artery AT2R function and expression. Angiotensin II dose-response curves were studied in rat perfused pressurized small-diameter arteries in the presence of losartan (AT1R antagonist Key Words: mineralocorticoid Ⅲ sodium Ⅲ hypertension Ⅲ vascular remodeling Ⅲ apoptosis T he renin-angiotensin-aldosterone system (RAAS) regulates vascular tone, body fluid volume, electrolyte balance, hormonal secretion, and neuronal activity. The biological effects of angiotensin II (Ang II), the main effector peptide in the vasculature, are mediated by at least 2 receptor isofoms. 1,2 The type 1 receptor (AT1R) mediates vasoconstriction, sympathetic facilitation, and trophic effects. The type 2 receptor (AT2R) is widely expressed during fetal development, whereas in the adult its expression has been detected in many different vessel types, including mesenteric, coronary, and renal arteries. 3-6 AT2R has opposite effects to those of AT1R, ie, it promotes cell apoptosis and inhibits cell proliferation. 6,7 AT2R also attenuates the pressor action of Ang II 8 and mediates vasodilation. 9,10 Recently, it has been shown that Ang II relaxes small mesenteric arteries via AT2R when AT1R are blocked. [11][12][13] Interestingly, the expression of AT2R is increased in several pathologic conditions such as vascular injury, 14 cardiac remodeling, congestive heart failure, and myocardial infarction. 15,16 It has been suggested that in adults the presence of AT2R in vascular tissues may be playing a role in vascular tone and/or tissue remodeling. [17][18][19] Therefore, a key and complex question that arises is how AT1R and AT2R expression are modulated. Several studies indicate interaction between Ang II and aldosterone, affecting the expression of ATRs. The expression of AT1R appears to be induced by Ang II in vascular smooth muscle, 4 and mineralocorticoids potentiate the action of Ang II in cultured rat vascular smooth muscle cells (VSMCs) by increasing the number of AT1R. 20,21 However, there are few data concerning the physiological regulation of AT2R expression. Dietary sodium depletion, which increases RAAS activity, enhances renal AT2 receptor function 10,22 and expression in both young and mature adult rats, mainly in the glomeruli and interstitial cells. 23 Induction of AT2R-mediated modulation of blood pressure was described in rats fed with a synthetic diet, an effect attributed to the stimulation of the RAAS. 8 Bonnet et al 24 have shown that Ang II infusion in the rat induces the expression of AT2R in the mesenteric vasculature. Nevertheless, it is not clear whether Ang II directly mediates the increased AT2R expression or if it is secondary to direct aldosterone action on arte...

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Section: Discussionsupporting

confidence: 54%

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

et al. 2005

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“…One potential mechanism for aldosterone-induced insulin resistance appears to be the transcriptional downregulation of the insulin receptor in addition to impairment of the intracellular insulin signaling (8). Glucocorticoid response elements (GRE) have been identified in the promoter of the insulin receptor gene (19), and interactions between activated MR and GRE may result in a negative transcriptional effect of the aldosterone over the insulin receptor gene (8). Aldosterone also activates glucocorticoid receptors in extrarenal tissue (37), which has direct negative effects on insulin metabolic signaling (23).…”

Section: Discussionmentioning

confidence: 99%

Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat

Lastra¹,

Whaley‐Connell²,

Manrique³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

104

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JR. Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat. Am J Physiol Endocrinol Metab 295: E110 -E116, 2008. First published April 29, 2008 doi:10.1152/ajpendo.00258.2007.-Renin-angiotensin-aldosterone system (RAAS) activation mediates increases in reactive oxygen species (ROS) and impaired insulin signaling. The transgenic Ren2 rat manifests increased tissue renin-angiotensin system activity, elevated serum aldosterone, hypertension, and insulin resistance. To explore the role of aldosterone in the pathogenesis of insulin resistance, we investigated the impact of in vivo treatment with a mineralocorticoid receptor (MR) antagonist on insulin sensitivity in Ren2 and aged-matched Sprague-Dawley (SD) control rats. Both groups (age 6 -8 wk) were implanted with subcutaneous time-release pellets containing spironolactone (0.24 mg/day) or placebo over 21 days. Systolic blood pressure (SBP) and intraperitoneal glucose tolerance test were determined. Soleus muscle insulin receptor substrate-1 (IRS-1), tyrosine phosphorylated IRS-1, protein kinase B (Akt) phosphorylation, GLUT4 levels, and insulin-stimulated 2-deoxyglucose uptake were evaluated in relation to NADPH subunit expression/oxidase activity and ROS production (chemiluminescence and 4-hydroxy-2-nonenal immunostaining). Along with increased soleus muscle NADPH oxidase activity and ROS, there was systemic insulin resistance and reduced muscle IRS-1 tyrosine phosphorylation, Akt phosphorylation/activation, and GLUT4 expression in the Ren2 group (each P Ͻ 0.05). Despite not decreasing blood pressure, low-dose spironolactone treatment improved soleus muscle insulin signaling parameters and systemic insulin sensitivity in concert with reductions in NADPH oxidase subunit expression/activity and ROS production (each P Ͻ 0.05). Our findings suggest that aldosterone contributes to insulin resistance in the transgenic Ren2, in part, by increasing NADPH oxidase activity in skeletal muscle tissue. Ren2 rat; mineralocorticoid receptor blockade THE ROLES OF INSULIN RESISTANCE in the pathophysiology of type 2 diabetes mellitus (T2DM) and the metabolic syndrome are well established (33,38), and exploration of the mechanisms leading to diminished insulin sensitivity is a field of active research.

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“…The enzyme complex includes membranebound subunits p22 phox and Nox2 (or 4 in the kidney), as well as cytosolic regulatory subunits p47 phox , p67 phox , and p40 phox and the small GTP-binding protein Rac1/Rac2, all of which are expressed in the kidney (18,39,41). There is an emerging body of evidence demonstrating that mineralocorticoids, like ANG II, may activate NADPH oxidase in various tissues (3,22,41). Results from the present investigation indicate that MR activation increases kidney tissue NADPH oxidase activity, in part via activation of membrane-bound Nox2 as well as the cytosolic p47 phox subunits.…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat

Whaley‐Connell¹,

Habibi²,

Wei³

et al. 2009

American Journal of Physiology-Renal Physiology

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CM, Sowers JR. Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat. Am J Physiol Renal Physiol 296: F1013-F1022, 2009. First published March 4, 2009 doi:10.1152/ajprenal.90646.2008.-Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6 -7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocytespecific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P Ͻ 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG-(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling. renal mineralocorticoid receptor; reduced nicotinamide adenine dinucleotide phosphate oxidase; oxidative stress; podocyte ALDOSTERONE, like angiotensin II (ANG II), exerts nongenomic actions in cardiovascular and renal tissues including the generation of reactive oxygen species (ROS), increases in inflammation, and impairment of insulin metabolic signaling and endothelial function, processes that promote glomerular disease and albuminuria (5,6,9,29,31). These adverse effects may result, in part, from mineralocorticoid receptor (MR)-and angiotensin type 1 receptor (AT 1 R)-mediated activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and redox-sensitive serine (Ser) kinases, such a...

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Transcriptional inhibition of the human insulin receptor gene by aldosterone

Cited by 37 publications

References 41 publications

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat

Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat

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