Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
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Obesity greatly increases risk of cardiovascular disease, metabolic syndrome, and diabetes mellitus. Most obese patients are unable to sustain appreciable weight loss; the body has a natural tendency to return to its previous weight. Although bariatric surgery is effective, it is not without risk. Until better treatments for obesity are available, management remains focused on lifestyle changes, drug therapy, and treating the metabolic complications of obesity. The main cause of metabolic dysfunction in obesity is visceral fat. Fat deposition in and around organs, skeletal muscle, and other tissues is thought to occur when subcutaneous adipose tissue stores are full. Creation of additional adipose-tissue stores is prevented by the mature adipocytes, which inhibit the differentiation of preadipocytes in a negative feedback loop. This inhibition is mediated, in part, by the renin-angiotensin system. Indeed, angiotensin II blockade has been shown to promote adipogenesis in vitro. Clinical studies are currently underway to investigate whether the angiotensin-II-receptor blocker telmisartan can stimulate adipogenesis, with the aim of diverting intramuscular fat back into adipose tissue and thereby restoring insulin sensitivity. If this effect can be demonstrated in humans, this type of agent might become the treatment of choice for obese or overweight people at risk of type 2 diabetes.
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PMID:The value of current interventions for obesity. 1858 Aug 64

Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise. The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment. The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.
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PMID:Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis. 1858 83

The increasing prevalence of obesity in the industrialized world is causing an alarming epidemic. Almost 70% of American adults are overweight or obese. The link between increasing body weight and hypertension is well established. Obesity hypertension through metabolic, endocrinic, and systemic hemodynamic alteration causes structural vascular and cardiac adaptations that trigger concentric, eccentric left ventricular hypertrophy and electrophysiological changes, which may increase the risk for congestive heart failure and sudden cardiac death as a result of arrhythmias. The increased renal blood flow in conjunction with a decreased renal vascular resistance causes renal hyperperfusion and hyperfiltration. Such changes lead to glomerulomegaly, focal segmental glomerulosclerosis, tubulointerstitial inflammation, and fibrosis that characterize the renal damage in obese hypertensive subjects. We propose that weight reduction, with the addition of other nonpharmacological approaches that included exercise and reduction in alcohol intake, should be the first choice to treat obesity hypertension. Salt restriction may be helpful only in salt-sensitive patients. The benefits of diet in obese patients include improvement of insulin sensitivity, reduction in sympathetic nervous and renin angiotensin system activities, and restoration of leptin sensitivity. As a consequence of these and other metabolic changes, the previously described systemic and renal hemodynamic alterations improved and the cardiovascular and renal morphological changes induced by obesity were lessened. After reviewing the medications available, we believe that owing to the cardiovascular and renal morbidity and mortality that characterized obesity hypertension, the ACEI or ARBs offer the best cardio-renal protection and should be the pharmacologic treatment of choice. If these alone do not control BP adequately, then a low-dose diuretic should be added as a second approach. Although we strongly believe in our proposal, more multicenter long-term clinical pharmacological trials are needed to evaluate the efficacy and safety of the antihypertensive approaches in the treatment of obesity hypertension.
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PMID:Obesity and hypertension: mechanisms, cardio-renal consequences, and therapeutic approaches. 1942 2

The biochemical and hormonal data in patients with adrenal incidentalomas were evaluated to compare the differences between adrenal adenomas and other benign lesions and to find the relationship between metabolic parameters and adrenal hormones. Ninety two patients (29men, age 20-90 years) with incidentally discovered unilateral or bilateral adrenal masses detected on CT were included in this study for the reasons others than adrenal pathology. Glycemia, cholesterolemia, triglyceridemia, hormonal evaluation including plasma ACTH, plasma aldosterone, plasma renin acitivity, overnight dexametasone test, ACTH test, free plasma metanephrines, urinary catecholamines were determined. In the group of patients with adrenal masses the prevalence of arterial hypertension was three fold higher, the prevalence of DM was approximately five fold higher and the prevalence of the overweight and obesity two fold higher than is reported in the general population. The most frequent adrenal masses were nonfunctional masses, the occurence of functional lesions was as follows: steroid enzymopathies (an exaggerated response of 17-OHP indicating a possible 21-hydroxylase deficiency), subclinical Cushing syndrome, primary aldosteronism and pheochromocytoma (5%, 2%, 2% and 1% respectively). There were no significant differences in evaluated data between patients with adenomas and hyperplasia and also no significant difference in evaluated data between lesions smaller than 3 cm and lesions greater than 3 cm. We did not find any correlations between plasma cortisol and lipid values. In this study we confirmed a higher prevalence of symptoms characteristic for different metabolic syndromes in these patients with adrenal incidentalomas, which indicate systematic screening for the metabolic syndrome including evaluation of the insuline resistance in this patients.
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PMID:Hormonal and metabolic evaluation of adrenal incidentalomas. 2251 94

We evaluated the effects of body weight (BW) loss on blood pressure (BP) in overweight non-obese patients with stage 1 hypertension. We enrolled 376 overweight (body mass index (BMI) >or=25 and <30 kg m(-2)) stage 1 hypertensive patients in this prospective 12-month trial. Each patient received tailored, low caloric dietary advice. After 6 months, patients with a BW reduction <5% were excluded. Body weight, BMI, BP, fasting plasma glucose (FPG), fasting plasma insulin (FPI), leptin (pL), renin and aldosterone levels were evaluated at baseline and after 6 and 12 months. In 222 patients who completed the study, a mean weight reduction of 8.1 kg reduced systolic blood pressure (SBP) by 4.2 mm Hg and diastolic blood pressure (DBP) by 3.3 mm Hg (P<0.05), which was accompanied by a significant decrease in FPI, pL and aldosterone levels (P<0.05). Larger SBP/DBP reductions were observed in 106 patients with normalized BMI (-5/-4.5 mm Hg, P<0.01) compared with the 116 patients who did not become normalized (-3.3/-1.6 mm Hg). The former also presented with greater decreases in FPG, FPI, pL, renin and aldosterone levels. Of the 106 patients who had normalized BMI, 52 also had normalized BP. Clinical and metabolic characteristics of these patients were similar to those of the 56 patients who did not have normalized BP. In overweight, mild hypertensive patients, weight loss was effective in reducing BP and in reversing some endocrinologic alterations associated with being overweight. Half of the patients who had normalized BMI also had normalized BP, which could indicate that these patients essentially did not have a form of hypertension but that these effects were instead secondary to being overweight.
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PMID:Effect of body weight loss and normalization on blood pressure in overweight non-obese patients with stage 1 hypertension. 2007 35

There is now solid knowledge for associating overweight and obesity with CKD. The risk for ESRD is progressively higher at increasing body mass index (BMI) levels and in extremely obese individuals such risk is 5 times higher than that in persons with normal body mass. Visceral fat, insulin resistance and inflammation are nicely inter-correlated in cross sectional studies in CKD patients but it is still untested whether the association between waist circumference or waist-hip ratio and CKD underlies a causal connection. Notwithstanding knowledge on the quantitative relationship between risk factors implicated in kidney damage is still limited, evidence derived from clinical series in patients with various renal diseases (IgA nephropathy, renal agenesia or post-nephrectomy) supports the hypothesis that obesity is an important factor in the progression and perhaps even in the initiation of CKD. Hyperfiltration is commonly found in obese persons. Due to high sympathetic activity, high levels of angiotensin II and hyperinsulinemia, obese persons display enhanced sodium reabsorption in the proximal tubule and are unable to rapidly increase sodium excretion. Enhanced proximal salt reabsorption determines a reduced delivery of sodium to the macula densa and therefore promotes afferent vasodilatation and enhanced renin synthesis. As a result of high local angiotensin II levels, the efferent arteriole is constricted in the obese. Glomerulomegaly and focal glomerulosclerosis represent the anatomical counterparts of glomerular hyperfiltration-hypertension. Hyperfiltration apart, evidence is emerging that inflammatory cytokines produced by fat cells trigger inflammation in the kidney and that this mechanism contributes to reduce renal function in the obese.
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PMID:Overweight, obesity and metabolic alterations in chronic kidney disease. 2008 47

Obesity has reached global epidemic proportions and is associated with major cardiovascular diseases and reduced overall survival. This paper reviews the metabolic and vascular consequences of dysfunctional adipocytokines in obesity as well as the pathological effects on blood pressure, cardiovascular structure and function. Despite this adverse association, numerous studies have documented an obesity paradox in which overweight and obese population with established cardiovascular disease have a better prognosis. There are potential explanations offered by literature for these puzzling data. For obese hypertensive patients the paradox is possibly linked to the lower systemic vascular resistance and plasma renin activity. In heart failure the excess body weight may confer some protective effects on mortality, due to a more metabolic reserve, higher levels of arterial pressure compatible with higher doses of cardioprotective medications, and a specific neuroendocrine profile with lower levels of circulating natriuretic atrial peptides, attenuated sympathetic nervous system and renin-angiotensin responses. For coronary heart disease and peripheral arterial disease the mechanisms are still uncertain. There are discussed a lesser severity of coronary lesions and left ventricular dysfunction, or a reduced prevalence of moderate-severe chronic obstructive pulmonary disease in patients selected for surgery. On the other hand, the constellation of data which supports purposeful weight reduction in the prevention and treatment of cardiovascular diseases, induces a controversial position regarding this new concept.
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PMID:[Obesity paradox]. 2019 67

Resistant hypertension is defined as uncontrolled hypertension despite intensive treatment with at least three antihypertensive agents, one of which ideally should be a diuretic. To determine the efficacy and safety of the selective aldosterone antagonist eplerenone in this population, we studied patients with resistant hypertension (clinic blood pressure [BP] >140 mm Hg systolic or >90 mm Hg diastolic on maximal doses of more than three antihypertensive agents, including a loop or thiazide diuretic). At baseline and after 12 weeks of eplerenone therapy (50 to 100 mg daily titrated to effect), patients underwent clinic and 24-hour BP measurements, serum potassium, plasma renin activity, and serum aldosterone measurements. Patients (n = 52) completing the trial averaged 62 +/- 10 years of age, were overweight (mean body mass index, 32.1 +/- 5.5 kg/m(2)), and had variable renal function (glomerular filtration rate, 106 +/- 38 mL/minute); 70% were men and 74% were non-Black. The mean number of antihypertensive agents at baseline was 3.7 +/- 0.8 (range, three to seven drugs) to achieve a clinic BP of 150.5/84.1 mm Hg. The mean serum aldosterone was 12.9 +/- 7.6 ng/mL and plasma renin activity was 2.3 +/- 2.7 ng/mL/hour. After eplerenone, the change from baseline in the clinic BP was -17.6/-7.9 mm Hg (P < .0001 for both systolic blood pressure [SBP] and diastolic blood pressure [DBP]) and in 24-hour BP was -12.2/-6.0 mm Hg (P < .0001 for both). The number of antihypertensive drugs decreased to 3.3 +/- 0.9 (range, one to seven agents). Plasma potassium increased by 0.30 +/- 0.45 mEq/L (P < .001), but there were only three instances in two patients of mild hyperkalemia (potassium >5.5 mEq/L, but <6.0 mEq/L), despite all patients being on a background therapy that included an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Reductions in clinic and ambulatory BP were related to baseline clinic and ambulatory BP values (r(2) > 0.3 for both SBP and DBP, P < .0001), weakly related to baseline serum aldosterone (r = -0.30; P = .05), and unrelated to plasma renin activity, age, gender, or race. In conclusion, eplerenone demonstrated substantial efficacy in treatment-resistant hypertension and was well-tolerated with modest changes in plasma potassium. Serum aldosterone and plasma renin activity did not predict BP responses to eplerenone in this population.
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PMID:Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. 2040 27

The prevalence of obesity, including childhood obesity, is increasing worldwide. Weight gain is associated with increases in arterial pressure, and it has been estimated that 60-70% of hypertension in adults is attributable to adiposity. Centrally located body fat, associated with insulin resistance and dyslipidemia, is a more potent determinant of blood pressure elevation than peripheral body fat. Obesity-related hypertension may be a distinct hypertensive phenotype with distinct genetic determinants. Mechanisms of obesity-related hypertension include insulin resistance, sodium retention, increased sympathetic nervous system activity, activation of renin-angiotensin-aldosterone, and altered vascular function. In overweight individuals, weight loss results in a reduction of blood pressure, however, this effect may be attenuated in the long term. An increasing number of community-based programs (including school programs and worksite programs) are being developed for the prevention and treatment of obesity. Assessment and treatment of the obese hypertensive patient should address overall cardiovascular disease (CVD) risk. There are no compelling clinical trial data to indicate that any one class of antihypertensive agents is superior to others, and in general the principles of pharmacotherapy for obese hypertensive patients are not different from nonobese patients. Future research directions might include: (i) development of effective, culturally sensitive strategies for the prevention and treatment of obesity; (ii) clinical trials to identify the most effective drug therapies for reducing CVD in obese, hypertensive patients; (iii) continued search for the genetic determinants of the obese, hypertensive phenotype.
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PMID:Obesity-related hypertension: epidemiology, pathophysiology, and clinical management. 2070 96

Obesity epidemic is in rise in almost every industrialized country and continues to be a growing problem worldwide. In fact, obesity per se has been recognized as a chronic disease. Consequently, there has been a cascade of metabolic changes initiated by the markedly risen prevalence that contributes to the increased incidence of diabetes, hypertension, and cardiovascular disease. Moreover, obesity is also associated with an increased risk of chronic kidney disease (CKD). The majority of the studies indicate a direct relationship between body mass index (BMI) and CKD risk. Moreover, current evidence emphasized the fact that central obesity measurements, such as waist circumference, could be a better predictor of CKD progression and mortality than BMI. The detrimental effects of obesity on kidney outcome have been recognized in nondialysis-dependent (NDD)-CKD patients. However, survival in overweight or obese CKD patients undergoing maintenance hemodialysis is paradoxically opposed compared with the general population. This "reverse epidemiology," however, is valid mainly for the inflammated end-stage renal disease (ESRD) patients. In fact, renal transplant recipients with higher BMI have inferior patient and graft survival compared to patients with lower BMI. This review also provides perspectives concerning the mechanisms associated with obesity, such as the renin-angiotensin-aldosterone system (RAAS) activation, and the role of leptin, adiponectin, fetuin-A, and adipose tissue, as factors that contribute to the development of CKD. Prevention strategies for CKD patients are also discussed and should be considered by clinicians.
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PMID:The role of obesity in kidney disease: recent findings and potential mechanisms. 2154 51


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