The renin angiotensin aldosterone system in hypertension: roles of insulin resistance and oxidative stress

Abstract

The relationship between HTNand other components of the CMSis complex. However, there is growing evidence that enhanced activation of the RAAS is a key factor in the development of endothelial dysfunction and HTN. Insulin resistance is induced by activation of the RAAS and resulting increases in ROS. This insulin resistance occurs in cardiovascular tissue and in tissues traditionally considered as targets for the action of insulin, such as muscle and liver. Indeed, there is a mounting body of evidence that the resultant insulin resistance in cardiovascular tissue and kidneys contributes to the development of endothelial dysfunction, HTN, atherosclerosis, CKD, and CVD.77 RAAS-associated signaling by way of the AT1R and MR, triggers tissue activation of the NADPH oxidase enzymatic activation and increased production of ROS. Oxidative stress in cardiovascular tissue is derived from both NADPH oxidase and mitochondrial generation of ROS, and is central to the development of insulin resistance, endothelial dysfunction, HTN, and atherosclerosis. Pharmacologic blockade of the RAAS not only improves blood pressure, but alsohas a beneficial impact on inflammation, oxidative stress, insulin sensitivity, and glucose homeostasis. Several strategies are available for RAAS blockade, including ACE inhibitors, ARBs, and MR blockers, which have been proven in the clinical trials to result in improved CVD and CKD outcomes. New research in these areas will allow for a better understanding of the relationship between HTN, insulin resistance, and activation of the RAAS, which could result in newer alternatives for a more comprehensive management of HTN in the setting of the CMS..

Fig. 1

Coordinated influence of obesity, insulin resistance, activation of the RAAS and the SNS in the pathophysiology of hypertension in the CMS.

Fig. 2

(Upper inset) Vascular effects of insulin (INS) or insulin like growth factor (IGF)-1 and counterregulatory effects of AT₁R and MR activation in endothelial cells. Insulin actions on the blood vessel are partially mediated by increased production of NO through phosphorylation and secondary activation of endothelial NO synthase (eNOS). AT₁R activation decreases the availability of NO by way of the induction of insulin resistance, diminishing eNOS mRNA stability, and promoting NADPH oxidase-induced ROS production. Mineralocorticoids also activate NAPDH oxidase with secondary O2⁻ production and consequent generation of peroxinitrite (ONOO−). Akt, PI3K/protein kinase B; GRE, glucocorticoid response element; Gq, G_q subunit; IRS, insulin receptor substrate; NOX2, catalytic subunit of NADPH oxidase; p22, p47, p40, and p67, subunits of NADPH oxidase; PH, pleckstrin homology domain; PIP, phosphatidylinositol phosphate; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; ROK, Rho kinase; SOD, superoxide dismutase. (Lower inset) Opposing effects of ANG II and aldosterone (Aldo) versus insulin/IGF-1 on VSMCs. Insulin and IGF-1 cause VSMC relaxation, whereas ANG II and mineralocorticoids cause contraction. MBS, myosin-bound serine; MLC, myosin light chain; MLCK, MLC kinase; Na/Ca exch, Na_/Ca2_ exchanger. (From Cooper SA, Whaley-Connell A, Habibi J, et al. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol 2007;293:2009–23; with permission.)