Regulate vascular tone and blood pressure
Figure 4 Pathway and effects of cytochrome P450 metabolites.
Endothelin (ET-1) is a potent vasoconstrictor and mitogen that is thought to play a role in the development of hypertension. The vascular endothelium is a major source of ET-1 production. ET-1 is believed to act in a paracrine manner on ETA and ETB receptors on smooth muscle that mediate contraction, cell proliferation, and hypertrophy. Activation of ETB receptors on endothelial cells stimulates the production of prostacyclin and NO to induce vasorelaxation. ETB receptor activation also inhibits sodium transport in renal tubules. Renal ET-1 is increased in saltsensitive hypertension and this effect is attenuated with ETA receptor antagonists.37 Interestingly, plasma ET-1 increases in hypertensive African American populations.37 ET-1 levels are also increased in streptozotocin-induced diabetic rats where the diabetes-induced vascular hypertrophy and remodeling is ET-dependent. Patients with diabetes or hypertension have elevated ET-1 levels, but do not exhibit positive correlations between ET-1 levels and blood pressure.38 These studies suggest ET-1 is involved in the pathogenesis of hypertension.
Aside from its potent vasoconstrictor effect, studies suggest that ET-1-induced vasoconstriction may be dependent, in part, on the production of superoxide anion. In vitro and in vivo studies have shown that ET-1 can stimulate superoxide anion formation in aortic rings.39 In cultured pulmonary artery smooth muscle cells, ET-1 increases superoxide production via stimulation of ETA receptor.40 Furthermore, ETA receptor blockade attenuates hypertension and reduced oxidative stress in salt-sensitive ETB receptor-deficient rats as an example of a high ET-1 model of hypertension.41 ET-1 also increases transforming growth factor-b (TGF-b), which plays a role in the vascular inflammation and fibrosis associated with hypertension and diabetes.42 Thus, beside its potent vasoconstrictor effect, ET-1 may produce further elevation in blood pressure via stimulation of superoxide and cytokines production.
The RAS contributes to the development and maintenance of hypertension and mediates renal injury by inducing systemic and glomerular hypertension. Synthesis of angiotensin II (AT-II) depends on the release of renin, primarily by juxtaglomerular cells in the kidney (Figure 5). The release of renin is regulated by the hydrostatic pressure sensed at the glomerular afferent arterioles, AT-II levels, and the quantity of sodium delivered to the macula densa. Plasma potassium, atrial natriuretic peptide, and endothelin levels also affect renin synthesis and release. Renin acts to cleave the liver angiotensinogen to angiotensin I (AT-I). ACE then converts AT-I to AT-II. This proteolytic enzyme is found in the endothelial cells of the lung, vascular endothelium, and cell membranes of the kidneys, heart, and brain. ACE also degrades vasodilator bradykinin to inactive fragments. Non-renin and non-ACE pathways also exist in the body allowing the production of AT-II either directly from angiotensinogen or from angiotensin I.43 The biologic actions of AT-II in the kidney are mediated by two well-characterized receptors: AT-II type 1 (AT-1) and AT-II type 2 (AT-2) receptors. In adult tissues, the AT-1 receptor is distributed in the vasculature, kidney, adrenal gland, heart, liver, and brain. In healthy adults, the AT-2 receptor is present only in the adrenal medulla, uterus, ovary, vascular endothelium, and
AT-1 receptor t Renal and systemic vasoconstriction f Sodium reabsorption ^ Inflammation t Reactive oxygen species + Hypertrophy and mitogenesis
Renal and systemic vasodilation
Figure 5 Pathway of the renin-angiotensin system (RAS) and its receptors.
distinct brain areas.43 The AT-1 receptor mediates the hemodynamic actions, endocrine functions, and mitogenic effects of angiotensin II in the kidney whereas the AT-2 receptor possesses vasodilatory effects and can modulate the action of AT-1 receptor.
Stimulation of the RAS increases sodium and water reabsorption through direct actions on renal tubular transport function 44.44 This effect is mainly due to the stimulation of AT-1 receptor by AT-II. Activation of angiotensin receptors by AT-II also stimulates synthesis of aldosterone in the zona glomerulosa of the adrenal gland. Aldosterone binds mineralocorticoid receptors expressed in the kidney and other organs leading to more salt and water retention. Aldosterone is involved in the development of obesity-induced hypertension. Plasma aldosterone levels are elevated in hypertensive patients with visceral obesity,45 and blocking mineralocorticoid receptors with the specific antagonist, eplerenone, inhibits development of high blood pressure in dogs fed a high-fat diet.46
Beside its water-retaining ability, AT-II is also a potent vasoconstrictor with growth-promoting properties. AT-II regulates blood pressure and fluid and electrolyte homeostasis. In the kidney, AT-II infusion increases renal microvascular resistance and enhances preglomerular reactivity during the early and established phases of hypertension. The increase in renal vascular resistance contributes to the increase in glomerular capillary pressure and inability of the kidney to properly excrete sodium and water. AT-II also reduces medullary blood flow and diminishes renal interstitial pressure. Collectively, these changes promote movement of sodium and fluid from the proximal tubule into the interstitium and systemic circulation and result in progressive increase in arterial blood pressure.
AT-II not only increases blood pressure via its vasoconstrictor effects, but also via the stimulation of ET-1 synthesis47 and increased ROS.48 Indeed, a potential mediator mechanism for the proinflammatory effects of AT-II may be due to increased superoxide generation via NADPH oxidase stimulation. The AT-II-stimulated increase in the activity of NADPH oxidase appears to be via the AT-1 receptor, as this effect can be blocked by preincubation of endothelial cells with the AT receptor blocker losartan.49
Aside from its hemodynamic effects, AT-II stimulates cell proliferation, inflammation, and tissue remodeling by enhancing the synthesis of profibrotic cytokines and growth factors. Infusion of AT-II causes vascular inflammation and endothelial dysfunction where these effects could be mediated by the activation of NFkB signaling and transforming growth factor-b (TGF-b).50 TGF-b stimulates production of other growth factors, causes proliferation of fibroblasts, and increases extracellular matrix protein synthesis. Both the production and activation of TGF-b are involved in glomerulosclerosis and interstitial fibrosis of the kidney.51 Collagen deposition is also enhanced through inhibition of proteases that normally function to degrade abnormal tissue proteins. In total, AT-II plays a critical role in the pathogenesis of hypertension and renal dysfunction not only via its direct vasoconstrictor and sodium retaining effects but also via nonhemodynamic effects such as increased ET-1, ROS, and inflammatory cytokine production.
The RAS plays a role in obesity-induced hypertension and its associated renal dysfunction. All components of the RAS are expressed by adipose tissue, and are upregulated in obesity.11 Obese persons have been shown to have high plasma renin activity, plasma angiotensinogen, ACE activity, and plasma AT-II levels. AT-II may also contribute to the increase glomerular injury and nephron loss associated with obesity. Angiotensin receptor blockers or ACE inhibitors blunt sodium retention and volume expansion in obesity. Studies in overweight patients with type 2 diabetes indicate that ACE and AT receptor blockers slow progression of renal disease.44 Given this information, as well as the fact that obesity is closely associated with the two main causes of end-stage renal disease, hypertension and diabetes, obesity-mediated angiotensin activation may greatly increase the risk for end-stage renal disease.
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