Pathogenesis Of Target Organ Damage Research Articles

Effects of inhibition of the renin-angiotensin system on hypertension-induced target organ damage: clinical and experimental evidence.

The dysregulation of renin-angiotensin-system (RAS) plays a pivotal role in hypertension and in the development of the related target organ damage (TOD). The main goal of treating hypertension is represented by the long-term reduction of cardiovascular (CV) risk. RAS inhibition either by angiotensin converting enzyme (ACE)-inhibitors or by type 1 Angiotensin II receptors blockers (ARBs), reduce the incidence of CV events in hypertensive patients. Actually, ACE-inhibitors and ARBs have been demonstrated to be effective to prevent, or delay TOD like left ventricular hypertrophy, chronic kidney disease, and atherosclerosis. The beneficial effects of RAS blockers on clinical outcome of hypertensive patients are due to the key role of angiotensin II in the pathogenesis of TOD. In particular, Angiotensin II through an inflammatory-mediated mechanism plays a role in the initiation, progression and vulnerability of atherosclerotic plaque. In addition, Angiotensin II can be considered the hormonal transductor of the pressure overload in cardiac myocytes, and through an autocrine-paracrine mechanism plays a role in the development of left ventricular hypertrophy. Angiotensin II by modulating the redox status and the immune system participates to the development of chronic kidney disease. The RAS blocker should be considered the first therapeutic option in patients with hypertension, even if ACE-inhibitors and ARBs have different impact on CV prevention. ARBs seem to have greater neuro-protective effects, while ACE-inhibitors have greater cardio-protective action.

Influence of therapy with trimetazidine on the state of the main vessels and microcirculation in patients with CHF and DM type 2. The results of the original study

Endothelial dysfunction plays a major role in the pathogenesis of target organ damage in patients with chronic heart failure (CHF) and type 2 diabetes mellitus (DM). The aim of the study was to evaluate the effect of trimetazidine on the parameters of the elasticity of the large arteries and microcirculation (MC) in patients with CHF and type 2 diabetes. 60 diabetic patients with CHF at the age of 45–70 years were included. All patients received baseline therapy of CHF and DM. Trimetazidine at a dose of 70 mg / day was prescribed for all patients of 1 group (n = 30) in addition to traditional treatment. The elastic properties of large arteries were evaluated by analyzing the velocity of the pulse wave propagation (SRV), and the MC parameters were studied. Results. Treatment with using of trimetazidine in addition to traditional treatment for 16 weeks significantly improved endothelial function, clinical state of patientsфтв the state of the parameters of the microcirculation.

Mitochondrial Dysfunction Contributes to Hypertensive Target Organ Damage: Lessons from an Animal Model of Human Disease.

Mechanisms underlying hypertensive target organ damage (TOD) are not completely understood. The pathophysiological role of mitochondrial oxidative stress, resulting from mitochondrial dysfunction, in development of TOD is unclear. The stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable model of human hypertension and of its vascular consequences. Pathogenesis of TOD in SHRSP is multifactorial, being determined by high blood pressure levels, high salt/low potassium diet, and genetic factors. Accumulating evidence points to a key role of mitochondrial dysfunction in increased susceptibility to TOD development of SHRSP. Mitochondrial abnormalities were described in both heart and brain of SHRSP. Pharmacological compounds able to protect mitochondrial function exerted a significant protective effect on TOD development, independently of blood pressure levels. Through our research efforts, we discovered that two genes encoding mitochondrial proteins, one (Ndufc2) involved in OXPHOS complex I assembly and activity and the second one (UCP2) involved in clearance of mitochondrial ROS, are responsible, when dysregulated, for vascular damage in SHRSP. The suitability of SHRSP as a model of human disease represents a promising background for future translation of the experimental findings to human hypertension. Novel therapeutic strategies toward mitochondrial molecular targets may become a valuable tool for prevention and treatment of TOD in human hypertension.

PP.25.09

Objective: Oxidative stress plays an important role in the pathogenesis of target organ damage (TOD) in hypertension, including renal injury. There is evidence, from human and animals’ models, that melatonin is involved in the regulation of blood pressure (BP) and may protect from development of high BP and TOD. Melatonin is one of the potent antioxidant molecules in nature. We hypothesized that melatonin protective effect in a high salt diet (HSD) rodent model is mediated by decreasing oxidative stress. Design and method: Ten Dahl salt sensitive (DSS) rats were fed normal chow [control (Ctrl)], 10 were fed HSD and 10 were fed HSD and got melatonin (Mel) (30/mg/kg/day) in their water for 8 weeks. Body and kidneys weights were measured at the end of the treatment. Renal function was evaluated by measurement of 24 hours urine protein excretion (n = 8–10). Glomerular injury index (GII) (fibrotic glomerulus/ 100 glomerulus) was evaluated in Masson's trichrom stained section of renal cortex (n = 5). Oxidative stress in the kidneys was evaluated by determining superoxide production using dihydroethidium (DHE) staining (n = 5). Results: Melatonin prevents weight loss caused by HSD (Ctrl-398 ± 8, HSD- 335 ± 17 Mel- 372 ± 7 gr. P < 0.05 HSD vs. Ctrl and Mel) but not the renal hypertrophy (Ctrl-0.58 ± 0.02, HSD- 0.87 ± 0.04 Mel 0.9 ± 0.03 gr. /tibia length, p < 0.05 Ctrl vs. HSD and Mel). Melatonin decreased the proteinuria seen in HSD fed rats (HSD- 50.7 ± 12 Mel- 22.3 ± 4.3 Protein/Cr, p < 0.05). Glomerular damage was significantly higher in the HSD group (GII 24 ± 6) than in Ctrl group (GII 0.8 ± 0.5, p < 0.05). Melatonin diminished significantly this damage (GII 3.6 ± 0.8, p < 0.05). Superoxide production was significantly higher in kidneys of HSD fed rats than in the Ctrl rats (99 ± 9 vs. 60 ± 7 relative fluorescent units (RFU)/μm2, respectively, p < 0.05). Treatment with melatonin decreased superoxide production in the kidneys of HSD fed rats (74 ± 5 RFU/ μm2, p < 0.05 vs. Ctrl and HSD). Conclusions: Treatment with melatonin abolishes the deleterious effect of HSD on the kidneys of HSD fed rats. Melatonin beneficial effect may be mediated by its anti-oxidative properties.

Arterial stiffness: insights from Framingham and Iceland.

To examine the putative measures of arterial stiffness and the mechanisms of adverse effects of stiffness on blood pressure and target organ damage using data from comprehensive hemodynamic profiles obtained in the Framingham Heart Study and the Age, Gene/Environment Susceptibility-Reykjavik Study. Once thought to be a consequence of longstanding hypertension, recent evidence suggests that aortic stiffness antedates and contributes to the pathogenesis of hypertension and target organ damage in the heart, brain, and kidneys. Carotid-femoral pulse-wave velocity (CFPWV) has emerged as the reference standard measure of aortic stiffness and a powerful predictor of cardiovascular disease risk. Augmentation index, a putative measure of arterial stiffness and wave reflection, has complex relations with stiffness and risk. Recent evidence suggests that wave reflection, which is a normal consequence of impedance mismatch between compliant aorta and stiff muscular arteries, is protective and limits the exposure of target organs to potentially harmful pulsatile energy. Aortic stiffening produces impedance matching that reduces wave reflection and exposes the microcirculation to excessive pulsatile stress, resulting in microvascular target organ damage and dysfunction. CFPWV provides a powerful new tool for risk stratification and elucidation of the pathogenesis of target organ damage in hypertension.

Pathogenesis of target organ damage in hypertension: role of mitochondrial oxidative stress.

Hypertension causes target organ damage (TOD) that involves vasculature, heart, brain and kidneys. Complex biochemical, hormonal and hemodynamic mechanisms are involved in the pathogenesis of TOD. Common to all these processes is an increased bioavailability of reactive oxygen species (ROS). Both in vitro and in vivo studies explored the role of mitochondrial oxidative stress as a mechanism involved in the pathogenesis of TOD in hypertension, especially focusing on atherosclerosis, heart disease, renal failure, cerebrovascular disease. Both dysfunction of mitochondrial proteins, such as uncoupling protein-2 (UCP2), superoxide dismutase (SOD) 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), calcium channels, and the interaction between mitochondria and other sources of ROS, such as NADPH oxidase, play an important role in the development of endothelial dysfunction, cardiac hypertrophy, renal and cerebral damage in hypertension. Commonly used anti-hypertensive drugs have shown protective effects against mitochondrial-dependent oxidative stress. Notably, few mitochondrial proteins can be considered therapeutic targets on their own. In fact, antioxidant therapies specifically targeted at mitochondria represent promising strategies to reduce mitochondrial dysfunction and related hypertensive TOD. In the present article, we discuss the role of mitochondrial oxidative stress as a contributing factor to hypertensive TOD development. We also provide an overview of mitochondria-based treatment strategies that may reveal useful to prevent TOD and reduce its progression.

Central hemodynamics in risk assessment strategies: additive value over and above brachial blood pressure.

Although the clinical relevance of brachial blood pressure (BP) measurement for cardiovascular (CV) risk stratification is nowadays widely accepted, this approach can nevertheless present several limitations. Pulse pressure (PP) amplification accounts for the notable increase in PP from central to peripheral arterial sites. Target organs are more greatly exposed to central hemodynamic changes than peripheral organs. The pathophysiological significance of local BP pulsatility, which has a role in the pathogenesis of target organ damage in both the macro- and the microcirculation, may therefore not be accurately captured by brachial BP as traditionally evaluated with cuff measurements. The predictive value of central systolic BP and PP over brachial BP for major clinical outcomes has been demonstrated in the general population, in elderly adults and in patients at high CV risk, irrespective of the invasive or non-invasive methods used to assess central BP. Aortic stiffness, timing and intensity of wave reflections, and cardiac performance appear as major factors influencing central PP. Great emphasis has been placed on the role of aortic stiffness, disturbed arterial wave reflections and their intercorrelation in the pathophysiological mechanisms of CV diseases as well as on their capacity to predict target organ damage and clinical events. Comorbidities and age-related changes, together with gender-related specificities of arterial and cardiac parameters, are known to affect the predictive ability of central hemodynamics on individual CV risk.

Abstract 551: Melatonin Prevents Renal Injury in a High Salt Diet Induced Hypertension Model by Decreasing Oxidative Stress.

Oxidative stress plays an important role in the pathogenesis of target organ damage (TOD) in hypertension, including renal injury. There is evidence, from human and animals' models, that melatonin is involved in the regulation of blood pressure (BP) and may protect from development of high BP and TOD . Melatonin is one of the potent antioxidant molecules in nature. We hypothesized that melatonin protective effect in a high salt diet (HSD) rodent model is mediated by decreasing oxidative stress. Ten Dahl salt sensitive (DSS) rats were fed normal chow [control (Ctrl)], 10 were fed HSD and 10 were fed HSD and got melatonin (Mel) (30/mg/kg/day) in their water for 8 weeks. Body and kidneys weights were measured at the end of the treatment. Renal function was evaluated by measurement of 24 hours urine protein excretion (n=8-10). Glomerular injury index (GII) (fibrotic glomerulus/ 100 glomerulus) was evaluated in Masson's trichrom stained section of renal cortex (n=5). Oxidative stress in the kidneys was evaluated by determining superoxide production using dihydroethidium (DHE) staining (n=5). Melatonin prevents weight loss caused by HSD (Ctrl-398±8, HSD- 335±17 Mel- 372±7 gr. P&lt;0.05 HSD vs. Ctrl and Mel) but not the renal hypertrophy (Ctrl-0.58±0.02, HSD- 0.87±0.04 Mel- 0.9±0.03 gr. /tibia length, p&lt;0.05 Ctrl vs. HSD and Mel). Melatonin decreased the proteinuria seen in HSD fed rats (HSD- 50.7±12 Mel- 22.3±4.3 Protein/Cr, p&lt;0.05). Glomerular damage was significantly higher in the HSD group (GII 24±6) than in Ctrl group (GII 0.8±0.5, p&lt;0.05). Melatonin diminished significantly this damage (GII 3.6±0.8, p&lt;0.05). Superoxide production was significantly higher in kidneys of HSD fed rats than in the Ctrl rats (99±9 vs. 60±7 relative fluorescent units (RFU)/μm 2 , respectively, p&lt;0.05).Treatment with melatonin decreased superoxide production in the kidneys of HSD fed rats(74±5 RFU/ μm 2 , p&lt;0.05 vs. Ctrl and HSD). Treatment with melatonin abolishes the deleterious effect of HSD on the kidneys of HSD fed rats. Melatonin beneficial effect may be mediated by its anti-oxidative properties.

Hypertensive heart disease

Hypertensive heart disease

Cardiovascular effects of prorenin blockade in genetically spontaneously hypertensive rats on normal and high-salt diet

Recent reports have demonstrated a potential role of tissue prorenin in the pathogenesis of cardiovascular and renal damage. This study was designed to examine the role of prorenin in the pathogenesis of target organ damage in spontaneously hypertensive rats (SHRs), the best naturally occurring experimental model of essential hypertension. To this end, we studied 20-wk-old male SHRs receiving a normal diet and 8-wk-old male SHRs given food with 8% NaCl. One-half the rats in each group were given prorenin inhibitor (PRAM-1, 0.1 mg.kg(-1).day(-1)) via osmotic minipumps; the other half served as controls. Arterial pressure, left ventricular function, cardiovascular mass indexes, cardiac fibrosis, and renal function were examined at the end of the experiment. Arterial pressure was unaffected by PRAM-1 in rats on either regular or salt-excess diets. In those rats receiving a normal diet, the blockade of prorenin activation consistently reduced left ventricular mass but affected no other variable. Salt-loaded rats given PRAM-1 for 8 wk demonstrated (1) reduced serum creatinine level, (2) decreased left ventricular mass, (3) improved left ventricular function, and (4) reduced left ventricular fibrosis. These data demonstrated that the blockade of nonproteolytic activation of prorenin exerted significant cardiovascular and renal benefit in SHRs with cardiovascular damage produced by salt excess and suggested that the activation of cardiovascular or renal prorenin may be a major mechanism that mediates cardiac and renal damage in this form of accelerated hypertension.

Nephroprotective effect of bosentan in diabetic rats.

Previous studies have suggested that endothelins could be involved in the pathogenesis of target organ damage in diabetes. The aim of this study was to evaluate the possible protective effect of Bosentan, an antagonist of endothelin receptor, on the kidney of diabetic rats. The study comprised a control group of 10 WKY rats and a group of 22 WKY rats in which diabetes was induced by streptozotocin i.v.; 10 rats were the control group. Diabetic rats received insulin and mean blood glucose was approximately mS 400 mg/dl throughout the study; they were divided into two groups: 11 rats received Bosentan 100 mg/kg/die by gastric gavage and 11 received vehicle for 1 month. Twenty-four hour urine collection was performed before and at the end of the study. Urinary protein excretion rate was expressed as microg urinary protein/mg urinary creatinine. The renal collagen I, fibronectin, and TGFbeta were evaluated by means of immunochemistry. The statistical analysis of the results demonstrates that Bosentan has prevented the increase in urinary protein excretion and that of renal immunoreactive collagen I, fibronectin, and TGFbeta induced by diabetes without reducing blood pressure. This study suggests a new clinical application for the antagonists of endothelin receptors.