Studies have demonstrated significant renal hemodynamic changes in hypertension and diabetes, e.g., decreased renal blood flow, increased renal vascular resistance, elevated glomerular hydrostatic pressure, and proteinuria. The exact mechanisms for renal dysfunction require further investigation and are thought to involve many factors such as activation of the renin-angiotensin system (RAS), enhanced sympathetic activity, and impaired nitric oxide signaling. All these factors lead to endothelial dysfunction and the progression of end-stage renal disease (Figure 3).
The sympathetic nervous system is an important regulator of cardiovascular function. Its activity is determined by psychological, neuronal, and humoral factors. Activation of neurohumoral systems as well as impairment of local
^ Renin-angiotensin system
A Sympathetic ' nerve activity t ET-1 t HETEs t
Inflammatory cytokines t ROS I NO I EETs
Salt and water retention
Hypertension and renal dysfunction
Figure 3 Mechanisms of obesity-induced hypertension.
regulatory mechanisms plays a significant role in the pathogenesis and prognosis of hypertension and cardiovascular diseases. The sympathetic nervous system activity increases with age, independent of disease state.18 Elevated sympathetic activity correlates with hypertension, insulin resistance, and risk of coronary heart diseases.19 The sympathetic nervous system activity contributes to the development of hypertension in early stages of the disease. Essential hypertension is thought to be associated with an enhanced sympathetic activity triggered at the level of the central nervous system in a complex manner.20 Sympathetic activation leads to vasoconstriction and increase in blood pressure mediated by a-adrenoceptors on smooth muscle cells, whereas effects on the heart are mediated by ^-adrenoceptors. The sympathetic nervous system also interacts with the RAS and the vascular endothelium. Stimulation of the b1-adrenoreceptor of the juxtaglomerular apparatus leads to activation of the RAS via elevation of renin release; this mechanism increases blood pressure as well as sodium and water retention. Overall, stimulation of sympathetic outflow increases blood pressure, and impairs renal pressure natriuresis. Therefore, it is likely that interference with neuronal pathways involved in the regulation of sympathetic activation at the level of the central nervous system may reduce blood pressure and cardiovascular risk.
Obesity is one of the main causes of renal dysfunction being characterized by increased sympathetic activity. Increased blood pressure associated with obesity is also accompanied by impaired natriuresis which could be attributed to the increase in renal sodium reabsorption.11 In chronic obesity, the increase in arterial pressure and glomerular hyperfiltration can lead to glomerular injury, gradual loss of renal function, and further impairment of renal pressure natriuresis. The increase in sodium reabsorption associated with weight gain could be the consequence of elevated renal sympathetic activity, activation of the RAS, and altered intrarenal physical forces. Overall, weight gain is associated with increased sympathetic activity and combined a- and ^-adrenoceptor blockade markedly attenuates the elevation in blood pressure during the development of diet-induced obesity in animals as well as in obese hypertensive individuals.21
Recent studies have focused on exploring the mechanisms by which obesity increases sympathetic outflow. One of these is hyperleptinemia. Leptin can regulate energy balance by decreasing appetite and stimulating thermogenesis via sympathetic stimulation. Acute infusion of leptin increases sympathetic activity and the hypertensive effect of leptin was completely abolished by combined a- and ^-adrenoceptor blockade.22 Hyperinsulinemia also plays a role in the activation of the sympathetic nervous system associated with obesity. In rats, insulin causes an enhancement of sympathetic activity in different tissues such as the kidney.23 High circulating levels of free fatty acids in obese subjects may participate in the activation of the sympathetic nervous system. Collectively, these data suggest that leptin, hyperisulinemia, and increased plasma free fatty acids could contribute to the activation of sympathetic system in obese subjects.
Endothelial dysfunction commonly occurs in obesity, type 2 diabetes, and hypertension. The endothelium acts to regulate vascular homeostasis by maintaining a balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell proliferation and migration, and inhibition of platelet activation, adhesion, and aggregation.24 Essential hypertension was first recognized to cause endothelial dysfunction early in the last decade where the increase in blood pressure has a direct influence on vascular function independent of other cardiovascular risk factors. Dysfunction of the endothelium could be due to decreased vasodilatory mediators and/or increased vasoconstrictor mediators. Factors that lead to reduction of vasodilation and endothelial dysfunction include a reduction in nitric oxide (NO) production, increased oxidative stress, a decrease in NO bioavailability; decreased prostacyclin levels, and a reduction of hyperpolarizing factors. Inflammatory responses also play a role in endothelial dysfunction as evidenced by the upregulation of adhesion molecules, generation of chemokines and production of plasminogen activator inhibitor-1. Vasoconstrictor peptides such as angiotensin and endothelin-1, hypercholesterolemia, and hyperglycemia contribute to endothelial dysfunction. Damage to the endothelium is an important risk factor for cardiovascular and renal diseases because it leads to structural changes such as thickening of the intima and media of the vessel wall. Because endothelial dysfunction is a complex process that results in hypertension and involves many factors, studies have focused on new approaches to improve endothelial dysfunction and slow he progression of hypertension.
Vascular tone is maintained by release of numerous dilator and constrictor substances where NO is the major vasodilator. The hallmark of endothelial dysfunction is impaired endothelium-dependent vasodilation. NO is formed by endothelial cells from L-arginine via the enzymatic action of endothelial NO synthase (eNOS), which is located in cell membrane caveolae. The protein caveolin-1 binds to calmodulin to inhibit activity of eNOS. The binding of calcium to calmodulin displaces caveolin-1, activating eNOS and leading to production of NO, which diffuses to vascular smooth muscle and causes relaxation by activating guanylate cyclase, to increase cyclic guanosine monophosphate (cGMP) levels which in turn produce a vasodilatory response.25
NO signaling is impaired in diabetic and hypertensive animal models with renal dysfunction such as stroke-prone spontaneously hypertensive rats and deoxycorticosterone acetate (DOCA)-salt hypertensive rats.26 Many factors contribute to the impairment of NO signaling in these models including decreased L-arginine bioavailability, decreases in the cofactors required for NO synthesis such as tetrahydropiopterin, and/or increased production of superoxide, which scavenges NO. NO production could also be regulated by posttranslational phosphorylation of serine-threonine residues on eNOS in experimental models of hypertension, diabetes, and obesity.27
Oxidative stress is defined as an imbalance between prooxidants and antioxidants. Reactive oxygen species (ROS) are intermediary metabolites that are normally produced in the course of oxygen metabolism. There are many reactive oxygen species that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Oxidative stress increases during hypertension due to increased production of ROS such as superoxide, hydroxy radical, and hydrogen peroxide and/or decreased superoxide dismutase (SOD), which scavenges ROS. Most recent attention has been given to the role of superoxide. There are many enzymatic sources of superoxide including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. ROS can react with and denature proteins, lipids, nucleic acids, carbohydrates, and other molecules leading to inflammation, apoptosis, fibrosis, and cell proliferation. However, under normal conditions, ROS play a critical role as signaling molecules, and ROS produced by activated leukocytes and macrophages are essential for defense against invading microorganisms. The excess production of ROS and/or impaired antioxidant defense capacity leads to oxidative stress, which predisposes tissue damage and endothelial dysfunction.
Oxidative stress is a common manifestation of cardiovascular and renal complications. For example, it is involved in the pathogenesis of endothelial dysfunction and atherosclerosis.28 This could be attributed to the ability of superoxide to scavenge NO and reduce its vasodilatory response. Oxidative stress is present in patients with mild to moderate renal insufficiency, as well as those with end-stage renal disease. Increased ROS production has also been shown in patients with essential, malignant, and renovascular hypertension. Agarwal eta/29 reported an increase in plasma levels of malondialdehyde, a marker of oxidative stress, in patients with chronic renal failure compared with those with essential hypertension despite similar blood pressure suggesting that inflammation and altered cellular redox state could be the reasons for the increase in oxidative stress. NADPH oxidase has emerged as the main source of ROS in the cardiovascular system. It is well established that oxidative stress can cause inflammation and inflammation can cause oxidative stress. For example, oxidative stress activates the transcription factor, nuclear factor kappa B (NFkB), leading to the generation of proinflammatory cytokines and activation of ROS generation by leukocytes and macrophages. Overall, increases in ROS result in endothelial dysfunction via decreased NO levels, increased inflammatory cytokines production, and/or direct oxidative and nitrosative damage to the cell.
Inflammation is an important contributor to the renal injury and endothelial dysfunction observed in hypertension and obesity. Elevated circulating levels of IL6 and TNF-a are observed in obesity and metabolic syndrome patients. IL6 stimulates the central and the sympathetic nervous system, which may result in hypertension.30 IL6 induces increases in hepatic triglyceride secretion in rats. IL6 also stimulates the production of C-reactive protein in liver and plasma levels of this protein are a good predictor of vascular inflammation. Another cytokine linked to obesity is TNF-a. TNF-a is overexpressed in the adipose tissue of obese patients, as compared with tissues from lean individuals. A positive correlation has been found between serum TNF-a concentration and both systolic blood pressure and insulin resistance in subjects with a wide range of adiposity. TNF- a acutely raises serum triglyceride levels in vivo by stimulating very low-density lipoprotein (VLDL) production and hence it can play role in the increased incidence of obesity. Upregulation of TNF-a secretion occurs in peripheral blood monocytes from hypertensive patients. TNF-a is important as it activates the transcription factor NFkB, resulting in increased expression of adhesion molecules and chemokines, e.g., monocyte chemoattractant protein-1 (MCP-1). Increased expression of MCP-1 and adhesion molecules leads to vascular inflammation and dysfunction, which in turn participates in the elevation in blood pressure and renal injury in hypertension and diabetes. As inflammatory cytokines play a key role in hypertension, insulin resistance, and obesity, future therapeutic efforts should focus on the possibility of using anti-inflammatory therapy for the treatment of nephropathy associated with obesity and hypertension.
126.96.36.199.6 20-Hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids
Arachidonic acid is metabolized by cytochrome P450 (CYP450) enzymes in the kidney, liver, heart, brain, and peripheral vasculature to epoxyeicosatrienoic acids (EETs) and the hydroxyeicosatetraenoic acids (HETEs) 19-HETE and 20-HETE. Enzymes of CYP450 4A and 4F families catalyze the formation of the potent vasoconstrictor metabolite 20-HETE, and enzymes of CYP450 2C and 2J families catalyze the formation of the potent vasodilator metabolites EETs that possess antihypertensive activity. EETs and 20-HETE influence both renal function and peripheral vascular tone and are also involved in the long-term control of blood pressure (Figure 4).32
20-HETE is a potent vasoconstrictor metabolite enhancing the vasoconstrictor actions of several hormones that regulate blood pressure including angiotensin II, endothelin, and 5HT. 20-HETE depolarizes vascular smooth muscle cells by inhibiting calcium-activated potassium channels and increases the conductance of L-type calcium channels, both effects leading to increased calcium entry and increased blood pressure. Additional effects of 20-HETE include mediation of the myogenic response of small cerebral and renal arteries to elevations in transmural pressure and the autoregulation of cerebral and renal blood flow and GFR. 20-HETE contributes to the elevation in peripheral vascular tone and vascular reactivity in angiotensin II hypertension. Chronic administration of angiotensin II increases 20-HETE production and this coincides with the development of hypertension. Additionally, blocking formation of 20-HETE attenuates the development of hypertension.32 In renal tubules 20-HETE produces natriuretic and antihypertensive effects by inhibiting sodium-potassium-ATPase, leading to diuresis and a fall in blood pressure. Induction of renal 20-HETE by fibrates lowers blood pressure and improves renal function in Dahl-salt sensitive rats while inhibition of 20-HETE promotes development of salt-sensitive hypertension
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