Angiotensin I converting enzyme and kinin–hydrolyzing enzymes along the rabbit nephron

Angiotensin I converting enzyme and kinin–hydrolyzing enzymes along the rabbit nephron. Angiotensin I converting enzyme (ACE) and kininase activities were measured in various segments of the rabbit nephron. ACE was determined with tritiated hippuryl-glycylglycine as substrate. Lysyl-bradykinin (LBK) hydrolysis (kininase activity) was measured by radioimmunoassay. ACE was only found in the glomerulus and in the two parts of proximal tubule: the convoluted proximal tubule and the pars recta (PR). It was distributed along a concentration gradient which increased from the glomerulus to PR. Kininase activity was found in both proximal and distal parts of the nephron. Besides intense LBK-hydrolyzing activity in the proximal tubule, a kininase activity was also found in the medullary collecting tubule (MCT). Kininase activity in the glomerulus and the proximal tubule was completely inhibited by chelating agents. Captopril inhibited this activity only in the PR and at high concentrations (above 10-7 M). These results indicate that several types of enzymes other than ACE hydrolyze kinins in the glomerulus and in the proximal tubule. The contribution of ACE to kinin hydrolysis appears only minimal. The kininase activity found in MCT was different from ACE and other proximal tubule kininases because it was not inhibited by chelating agents. This kininase may play a physiological role in inactivating the kinins formed by kallikrein at or beyond the connecting tubule

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Take a deep breath and check your heart

International audienceThe physician is often faced with diagnosing causes of dyspnea in its clinical practice. Patients may spontaneously complain from shortness of breath but otherwise, and often, the symptom has to be recognized and extracted from patient’s history through questioning (Banzett R.B., & Schwartzstein, 2015). In most cases, dyspnea occurs because normal breathing frequency and amplitude does not allow delivering appropriate oxygen supply to tissues and maintaining low blood carbon dioxide or hydrogen ions (pH) concentration, at rest and/or at exercise. This occurs especially in the brain, triggering chemoreceptor stimulation and causing feeling of discomfort. Besides several different conditions pertaining to respiratory, haematological or neurological disorders, coronary insufficiency and heart failure are leading causes of dyspnea. Dyspnea is then due to non-adaptation of cardiac output to peripheral organ metabolism and, in congestive heart failure, to pulmonary hemodynamic alterations

Rôle physiologique de la kallicréine rénale

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Pharmacogenetic and Pharmacogenomic Studies

The topics discussed in this article are concerned with studying genomic polymorphism and dentifying new therapeutic targets, the role of genetics in preclinical and clinical drug development, and cultural, regulatory and logistical aspects of the development of pharmacogenetics in France. The conclusions are that from a physiological, biochemical or genomic point of view, the study of human genetic polymorphism has obvious potential value for drug development, because it can help to identify new therapeutic targets, and to predict drug efficacy and tolerability more effectively. There are already several examples of the latter approach, which relies on studying the genetic variability of enzymes involved in drug metabolism, and that of the effector molecules of the pharmacological activity. Pharmacogenetics could eventually make it possible to personalise drug treatments, as methods for analysing genes are simplified and their cost reduced. To help attain this still far-off goal, certain recommendations have been proposed

Pharmacogénétique, étude du génome et développement des médicaments

Les sujets discutés concernent l'étude du polymorphisme du génome et l'identification de nouvelles cibles thérapeutiques, la place de la génétique dans le développement préclinique et clinique des médicaments, et les aspects culturels, réglementaires et logistiques du développement de la pharmacogénétique en France. Les conclusions sont que l'étude du polymorphisme génétique humain, au plan physiologique, biochimique ou génomique, a un intérêt potentiel évident pour le développement des médicaments car elle peut aider à identifier de nouvelles cibles thérapeutiques, et à mieux prévoir l'efficacité et la tolérance des médicaments. Cette dernière approche, qui repose sur l'étude de la variabilité génétique des enzymes impliquées dans le métabolisme des médicaments, et de celle des effecteurs moléculaires de l'action pharmacologique, est déjà illustrée par plusieurs exemples. La pharmacogénétique pourrait permettre, à terme, l'individualisation des traitements médicamenteux, grâce à la simplification des méthodes d'analyse des gènes et à la diminution de leur coût. Pour aider à approcher ce but encore lointain, certaines recommandations sont faites

Kallikrein/K1, Kinins, and ACE/Kininase II in Homeostasis and in Disease Insight From Human and Experimental Genetic Studies, Therapeutic Implication

International audienceKallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice