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High blood pressure (HBP) is common in diabetic patients and significantly increases complications of diabetes and cardiovascular risk. It is therefore particularly important to routinely screen and treat HBP in these patients. Blood pressure targets in this population (

High blood pressure (HBP) is common in diabetic patients and significantly increases complications of diabetes and cardiovascular risk. It is therefore particularly important to routinely screen and treat HBP in these patients. Blood pressure targets in this population (130/80mmHg) should be adapted to age and comorbidities. The therapeutic strategy has expanded beyond renin-angiotensin-aldosterone system inhibitors in the diabetic population, with treatments which decrease cardiovascular and renal risk, such as SGLT2 inhibitors, GLP-1 receptor agonists, and soon finerenone.L’hypertension artérielle (HTA) est fréquente chez les patients diabétiques et augmente de manière considérable les complications du diabète et le risque cardiovasculaire. Il est donc particulièrement important de dépister de manière systématique et de traiter l’HTA chez ces patients. Les cibles tensionnelles dans cette population (130/80 mmHg) doivent être adaptées à l’âge et aux comorbidités. Dans la population diabétique, l’arsenal thérapeutique s’est élargi au-delà des inhibiteurs du système rénine-angiotensine-aldostérone, avec des traitements qui influencent le pronostic cardiovasculaire et rénal, comme c’est le cas pour les inhibiteurs du SGLT2, les agonistes des récepteurs du GLP-1 et, bientôt, la finérénone.

Both renin-angiotensin-aldosterone system inhibitors (RAASi) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i, gliflozins) reduce the risk of heart failure and of progressing towards end-stage renal disease, especially in patients with type 2 diabetes (T2D). Positive results reported in patients with T2D have been confirmed in people without diabetes. These two pharmacological classes now occupy a privileged place in international guidelines, in diabetology, cardiology and nephrology. The present article describes similarities and differences between these two types of medications. It emphasizes the importance of combining both approaches in order to optimize the cardiovascular and renal prognosis, while maintaining a good safety profile.Les inhibiteurs du système rénine-angiotensine-aldostérone (iSRAA) et les inhibiteurs des cotransporteurs sodium-glucose de type 2 (iSGLT2, gliflozines) réduisent le risque d’insuffisance cardiaque et de progression vers l’insuffisance rénale terminale, notamment chez les patients avec un diabète de type 2 (DT2). Les effets positifs rapportés chez les patients DT2 ont été confirmés chez les personnes non diabétiques. Ces deux classes pharmacologiques occupent maintenant une place de choix dans les recommandations internationales, en diabétologie, en cardiologie et en néphrologie. Cet article fait le point sur les similitudes et les différences entre ces deux familles médicamenteuses. Il insiste sur l’importance de les combiner pour optimiser le pronostic cardiovasculaire et rénal, tout en maintenant un bon niveau de sécurité.

The kidney plays a major role to maintain the constancy of the "milieu intérieur" by adjusting the urinary excretion of water and solutes to the requirement of the body balance. This function is coordinated with elimination of waste products generated among others by the catabolism of proteins and nucleic acids. To cope with these two major functions, the human kidneys generate each day about 180 L of ultrafiltrate from plasma and reabsorbs the vast majority of filtered water and solutes to excrete daily about one-two liter(s) of urine containing concentrations of sodium, potassium and chloride ranging from 20 to 200 mM. The final adjustment of urine composition is finely tuned along the aldosterone-sensitive distal nephron (ASDN) which includes the distal convoluted tubule and the collecting system (connecting tubule and collecting duct). Sodium reabsorption is predominant along the distal tubule if potassium must be spared, or along the collecting system when large amounts of potassium must be secreted. Nephrotic syndrome is characterized by heavy proteinuria consecutive to a glomerular injury, associated with renal sodium and water retention taking initially place along ASDN and leading to edema.Rôle du néphron distal dans le contrôle du volume extracellulaire en condition physiologique et dans le syndrome néphrotique.Les reins jouent un rôle majeur dans le maintien de la composition du milieu intérieur. Cette fonction est coordonnée avec l’élimination des déchets du métabolisme, impliquant la production par les reins d’environ 180 litres de filtrat par jour et la réabsorption de la grande majorité de l’eau et des solutés filtrés. L’ajustement final de la composition de l’urine est réalisé dans le segment distal sensible à l’aldostérone (ASDN), qui inclut le tube contourné distal et le système collecteur. La réabsorption de sodium prédomine dans le tube distal si le potassium doit être épargné, ou dans le système collecteur si le potassium doit être sécrété. Le syndrome néphrotique est caractérisé par une protéinurie massive causée par des lésions glomérulaires, associée à une rétention hydrosodée prenant place dans l’ASDN et induisant chez le patient des œdèmes parfois volumineux.

CME: Hypertension and the COVID-19 Pandemic: What to Consider in Medical Practice

In France, no consensus document on the management of persistent hyperkalaemia is currently available. Variability in clinical practices has been observed.A consensus statement on the definition and the management of persistent hyperkalaemia was developed by a Delphi panel of French nephrologists between December 2019 (26 voting participants among 40 invited panellists in first round) and June 2020 (20 voting participants among 26 panellists in second round).Persisting hyperkalaemia not controlled with current treatment strategies may be defined as the occurrence of two or more hyperkalaemia episodes within a year despite the administration of cation-exchange resins or loop diuretics during the same year. Some patient characteristics (diabetes, chronic kidney disease from stage 3B to stage 5 without dialysis, chronic heart failure) are associated with an increased risk of developing persistent hyperkalaemia. There is a medical need for the management of persistent hyperkalaemia in patients treated with renin-angiotensin-aldosterone system inhibitors that is not met by current treatment strategies (including available cation-exchange resins).The panel expressed a need for new treatment strategies validated by clinical trials.

The breakthrough of the secrets of hypertension and the renin-angiotensin-aldosterone system (RAAS) is one of the legends of medicine. The first chapter is the one of Tigerstedt's experiments about renin, and Loesch and Gollblatt's model of renal hypertension. The race to elucidate the mechanisms of angiotensin, angiotensinogen and the angiotensin conversion enzyme cascade, by Braun Menéndez and Page teams, is a second chapter. The puzzle of this elegant cascade is completed by aldosterone isolation by the collaboration of Tait spouses and Tadeus Rechstein. As a corollary of these findings, Conn made the first description of primary hyperaldosteronism. The elucidation of RAAS pathophysiology naturally led to the synthesis of the antihypertensive captopril by Ondetti and Cushman, thereby opening the modern era of ACE inhibitors and ARII blockers. In March 2020, a viral pandemic caused by SARS-Cov-2 ignites the entire planet. This new coronavirus uses the RAAS angiotensin conversion enzyme type 2 (ACE-2) as a gateway. The SARS-CoV-2/ACE-2 signalling pathway and its pathological effects on the cardio-respiratory and renal system of these patients initiate a new chapter. The interaction of SARS-Cov-2/ACE-2 axis with anti-hypertensive agents, as well as with ACE-2 activators and ACE-2 homologs, takes a part of an active international study searching for therapeutic targets. This modern research, summarized in this article, will further develop our knowledge of RAAS and, hopefully, will improve the management of COVID-19 patients.La percée des secrets de l’hypertension artérielle et du système rénine-angiotensine-aldostérone (SRAA) est une des histoires légendaires de la médecine. Les expériences de Tigerstedt sur la rénine, puis le modèle d’hypertension rénale de Loesch et de Gollblatt, constituent un premier chapitre. La course pour élucider le mécanisme de l’angiotensine, l’angiotensinogène et l’enzyme de conversion de l’angiotensine par les équipes de Braun Menéndez et de Page est un deuxième chapitre. Le puzzle de cette élégante cascade biochimique se complète par la description de l’aldostérone isolée par les époux Tait avec Tadeus Rechstein, et, comme corollaire, la description par Conn de l’hyperaldostéronisme primaire. La compréhension physiopathologique du SRAA amène naturellement à la synthèse de l’anti-hypertenseur captopril par Ondetti et Cushman, inaugurant l’ère moderne des inhibiteurs de l’enzyme de conversion de l’angiotensine (IEC) et des antagonistes des récepteurs AT1 de l’angiotensine 2 (ARAII ou sartans). En mars 2020, une pandémie virale déclenchée par le SARS-CoV-2 embrase la planète. Ce coronavirus utilise comme porte d’entrée cellulaire l’enzyme de conversion de l’angiotensine 2 (ACE-2) du SRAA. La voie de signalisation SARS-CoV-2/ACE-2 et ses effets, sur les systèmes cardio-respiratoire et rénal, ouvrent un nouveau chapitre. L’interaction de cet axe SARS-Cov-2/ACE-2 avec les antihypertenseurs, mais aussi les activateurs et homologues de l’ACE-2 font objet d’une étude internationale active, à la recherche de cibles thérapeutiques. Cette recherche, que nous synthétisons dans cet article, est destinée à développer notre connaissance sur le SRAA et, nous l’espérons, à améliorer peut-être la prise en charge des patients avec COVID-19.

Recurrent hyperkalaemia may result in underutilisation of renin-angiotensin-aldosterone system inhibitors. We report an analysis of French data from the PROKALE retrospective study, which assessed the management of recurrent hyperkalaemia in five European countries.A retrospective chart review including patients not on dialysis with two or more hyperkalaemia episodes≥5.5 mEq/L documented within a 12-month observation period was performed.In France, 115 physicians (57 nephrologists et 58 cardiologists) participated in the study and 295 patients were studied in this analysis. Mean age was 68 years; 212 patients (71.9%) had chronic kidney disease, 108 (36.6%) had chronic heart failure and 102 (34.6%) had diabetes mellitus. The mean number of documented hyperkalaemic episodes was 2.3. A total of 90 hospitalizations occurred during the observation period, of which 24 (26.7%) were directly related to a hyperkalaemic episode. At the time of the first documented hyperkalaemic episode, measures used for the management of hyperkalaemia included loop diuretics (144 patients [48.8%]), sodium/calcium polystyrene sulphonate (135 patients [45.8%]), a low-potassium diet (31 patients [10.5%]) and sodium bicarbonate (31 patients [10.5%]). Between the two consecutive hyperkalaemic episodes documented, the proportion of patients on renin-angiotensin-aldosterone system inhibitors treatment decreased from 42.4% to 34.6%.Renin-angiotensin-aldosterone system inhibitors treatment interruptions were observed in the setting of recurrent hyperkalaemic episodes. Recurrent hyperkalaemia is a major cause of hospitalizations. More effective strategies for the prevention of recurrent hyperkalaemia are needed.

Hypertension is a common clinical problem in patients with cancer. This is explained by its high prevalence in the general population, by the improvement in life expectancy in oncology patients thanks to the progress of anti-cancer therapies, but also by cancer therapy, which is sometimes burdened with cardiovascular toxicity. Early detection of hypertension and proper management are crucial to ensure the continuation of oncology treatment and to protect patients from the consequences of hypertension. Renin-angiotensin system blockers and calcium channel blockers are the first-line treatments.

ACE2 is not only an enzyme that counters the effects of the renin-angiotensin-aldosterone system (RAAS) but is also the entry receptor for SARS-CoV-2, the virus of the Covid-19 pandemic. Some experimental data suggest that ACE inhibitors and ARBs increase ACE2 levels, thus raising concerns on their security in Covid-19 positive patients. However, some studies have shown protection by these drugs in lower tract respiratory infections and ARDS. The actual consensus is to continue the treatment with RAAS inhibitors, abrupt withdrawal, especially in patients with cardiac or renal conditions, being hazardous in terms of cardiovascular outcomes, except in patients hospitalized in intensive care with hemodynamic instability. This position statement is actually unanimous among all international learned societies.L’enzyme de conversion de l’angiotensine ACE2 est le récepteur membranaire du virus SARS-CoV-2, permettant son entrée dans les cellules cibles. ACE2 est également une enzyme qui contrebalance les effets de l’axe classique angiotensine II et récepteur AT1 du système rénine-angiotensine. Cette double fonction a suscité des craintes par rapport à une augmentation du risque d’infection ou de complications chez les patient·es traité·es par cette classe d’antihypertenseurs. Toutefois il existe des arguments opposés faisant penser que ces médicaments seraient plutôt protecteurs dans certaines affections pulmonaires virales aiguës. Le consensus actuel est de ne pas interrompre ces médications, sauf chez les patient·es hospitalisé·es hémodynamiquement instables, au vu du danger d’une suspension brutale en cas de pathologie cardiaque ou rénale.

Type 2 diabetes has an increasing prevalence. Life expectancy is dominated by cardiovascular risk, which is the leading cause of death in these patients. Up to one third of diabetic patients will develop diabetic nephropathy related to micro-angiopathy. Renal impairment further increases cardiovascular risk. Reducing cardiovascular morbidity and mortality is a major public health issue, as well as early preventing and managing chronic kidney disease (CKD). Good glycemic control prevents the micro-vascular complications of the disease (retinopathy, nephropathy, etc.) and, more recently recognized through prolonged monitoring of the VADT cohort, prevents cardiovascular complications. Control of blood pressure and dyslipidemia are essential in primary or secondary cardiovascular prevention. In addition, the blockers of the renin-angiotensin system slow down the progression of the MRC. Elderly patients with chronic kidney disease (CKD) form another growing group of the nephrologist daily patient pool. Especially for very elderly patients with comorbidities, the question of favoring conservative treatment rather than starting or pursuing dialysis may arise. Survival and quality of life are indeed not necessarily better in elderly patients undergoing dialysis, complications can occur eventually leading to discontinuation, and are occasionally associated with a feeling of stubbornness. Creation of prognostic score is a useful tool to help the decision-making process. However, dialogue with the patient and his/her family, as well as multidisciplinary collaboration remain fundamentals to determine the most suitable care.

Hyperkaliaemia is a serious electrolyte disorder that is favored by many comorbidities, such as chronic renal failure or some treatments such as renin-angiotensin-aldosterone system blockers. The new oral treatments by chelation of intestinal potassium have demonstrated : 1) their effectiveness in the management of serum potassium by maintaining the treatments at optimal dosages ; 2) their safety of use by the absence of serious side effect and 3) the ease of use with a daily intake.L’hyperkaliémie est un trouble électrolytique grave favorisé par certaines comorbidités, comme l’insuffisance rénale chronique ou certains traitements tels que les bloqueurs du système rénine-angiotensine-aldostérone. Les nouveaux traitements oraux par chélation du potassium intestinal ont prouvé : 1) leur efficacité dans la gestion de la kaliémie en maintenant les traitements aux posologies optimales ; 2) leur sécurité d’emploi par l’absence d’effet indésirable grave et 3) la facilité d’emploi avec une prise quotidienne.

This clinical case draws attention to the importance of stopping some medications in case of gastrointestinal disturbances that could induce dehydration. The latter can provoke an acute renal failure, which may lead to a toxic accumulation of these pharmacological agents and/or increase their nephrotoxicity. This may induce a vicious circle that is potentially dangerous and even fatal. Three pharmacological classes that are widely used in clinical practice are considered as examples, metformin, inhibitors of the renin-angiotensin system and nonsteroidal anti-inflammatory drugs. For each of them, the pathophysiology of the complication will be briefly discussed. Some patient risk profiles where caution is mandatory will be also emphasized.Cette vignette clinique attire l’attention sur l’importance d’interrompre certains médicaments en cas de troubles digestifs susceptibles d’entraîner une déshydratation. En effet, cette dernière peut provoquer une insuffisance rénale aiguë qui va contribuer à une accumulation toxique de ces médicaments et/ou augmenter leur néphrotoxicité. Il peut s’ensuivre un véritable cercle vicieux, potentiellement dangereux, voire mortel. Trois classes de médicaments, très fréquemment prescrites, sont prises à titre d’exemple, la metformine, les inhibiteurs du système rénine-angiotensine et les anti-inflammatoires non stéroïdiens. Pour chacune d’entre elles, la physiopathologie de la complication sera brièvement discutée. Il sera également mis l’accent sur certains profils de risque de patients chez lesquels la plus grande prudence s’impose.

Summary Background Metabolic syndrome is a combination of symptoms including obesity, dyslipidaemia, glucose intolerance and hypertension. Oxidative stress appears to be a pathophysiological factor that links these signs and encourages progression towards heart failure and diabetes. Nox4 is a hydrogen peroxide nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform – found in various cardiovascular cells and tissues, but also in tissues such as the liver – which is involved in glucose and lipid homeostasis. Aims To test whether inhibition of the Nox4 enzyme could improve blood pressure and metabolic parameters in mice receiving either angiotensin II or a high-fat diet. Methods Systolic and diastolic arterial pressures, pulse rate and heart rate were obtained in 24 male mice (12 wild-type [WT] and 12 Nox4–/–) before and during 14 days of angiotensin II infusion. After angiotensin II infusion, cardiac histological remodeling was assessed. Weight and biochemical parameters were measured in 18 male and 18 female mice (nine WT and nine Nox4–/– per gender) after 10 weeks on a standard chow diet, then 15 weeks on a high-fat diet. Glucose tolerance and insulin sensitivity were tested at age 25 weeks. Results Knock-out animals did not demonstrate a baseline blood pressure phenotype, but blocking Nox4 protected against angiotensin II-mediated arterial and pulse pressure increases. No protection against angiotensin II-induced cardiac fibrosis was observed. From a metabolic point of view, Nox4 inhibition reduced plasma triglycerides in male and female mice under a chow diet. However, Nox4 deletion did not affect the metabolic profile under a high-fat diet in males or females, but increased glucose intolerance in females. Conclusion Our data identify Nox4 as a key source of radical oxygen species involved in hypertension and some metabolic problems.

IgA nephropathy is the most common form of primary glomerulonephritis worldwide and an important cause of chronic kidney disease and end-stage kidney failure. Its pathophysiology remains in part unsolved but it is recognized as an immune complex disease. Recent years have brought progress in the field through the discovery of several genetic susceptibility loci and the formulation of the multi-hit pathogenesis model. Presentation, clinical course and histology can be extremely variable, making any histological classification still difficult. Indeed, most therapeutic studies until now include patients based only on the severity of clinical criteria but the new classification of Oxford should change that. Only the management of patients with nephropathy with minimal change glomerular lesions and nephrotic syndrome, or extra-capillary glomerulonephritis and rapidly progressive renal failure, is consensual: Corticosteroids alone for the first and associated with immunosuppressive drugs for the latter. The recent Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guideline is still controversial, especially in light of the last clinical studies. Corticosteroid therapy can be discussed in patients with proteinuria greater than 1 g/day without renal failure. All IgA nephropathy patients should benefit from the global management of chronic glomerular disease, including a renin-angiotensin system blocker in the presence of hypertension or proteinuria.

Estimate the prevalence of resistant hypertension (rHTN) in uncontrolled hypertensive treated patients referred to a tertiary care center specialized for hypertension management.The study was prospective observational. Between January 2013 and April 2015, we recruited hypertensive treated patients, 18years age or older, under antihypertensive drugs since at least 12months, and referred to the hypertension unit of Tizi-ouzou university hospital for uncontrolled hypertension. rHTn was defined as an office blood pressure≥140mmHg despite a triple therapy including renin angiotensin system blockers, calcium antagonists and diuretics at optimal doses, since at least 4weeks.We screened 2367 patients with a mean age of 61.1±11.2years and 64.2% of men. Eight hundred forty-three (35.6%) patients had suboptimal treatment, 364 (15.4%) a poor adherence to treatment and 202 (8.5%) a white-coat effect. An excessive salt intake and a drug-related hypertension were identified in 281 (11.9%) and 36 (1.5%) patients, respectively. A secondary cause of hypertension was diagnosed in 468 (19.8%) subjects. Finally, only 173 patients showed a true rHTN requiring four drugs or more and its prevalence was 7.3% (CI 95%: 6.3-8.3).Less than one patient from ten referred in our center for uncontrolled hypertension had a true rHTN, and more than fifty percent of patients had pseudo-resistance. Most of patients with seemingly rHTN can reach blood pressure target provided they undergo thorough work up and care by a specialized team.

The 9th World Kidney Day, on 13 March 2014, was devoted to the topic of renal aging. The proportion of older people in the general population is increasing steadily worldwide, with the most rapid growth in developing countries. This demographic upheaval is a consequence of socioeconomic development and increasing life expectancy. Chronic kidney disease is an important public health problem characterized by poor health outcomes and very high healthcare costs. Chronic kidney disease is a major risk multiplier in patients with diabetes, hypertension, heart disease and stroke, all of which are key causes of death and disability among older people. The prevalence of chronic kidney disease is higher in the elderly, in whom it contributes to the effects of aging. The decrease in renal function with age also compounds the effects of renal disease, whether primary or secondary to systemic or urinary tract disorders. This physiological reduction in functional capacity affects the glomerular filtration rate and renal tubular functions, including water and salt regulation and also the elimination of many drugs. The aging kidney is much more sensitive to toxic insults, especially those due to nonsteroidal antiinflammatory drugs and iodinated contrast agents. Prevention of renal deterioration in the elderly is based on monitoring renal function, adapting medications, and maintaining a regular supply of water and salt.

Blockade of the renin-angiotensin system (RAS) with angiotensin-converting-enzyme (ACEI) inhibitors or angiotensin II receptor blockers (ARB) has become a major therapeutic tool. Due to internal counter-regulation, however, this system cannot be fully blocked by targeting only one of its components. Instead of increasing the doses of an ACEI, an ARB or a renin inhibitor, blocking RAS at two successive levels neutralizes the consequences of internal counter-regulation and thus provides a more complete blockade with more pronounced biological effects. Additive effects on blood pressure lowering and on renin secretion during combined administration of RAS blockers were first demonstrated in normotensive subjects and in various experimental models of hypertension, heart failure and renal failure. Although combined RAS blockade provided an additional hemodynamic response and more complete neutralization of the cellular effects of angiotensin II, no benefit was observed in terms of cardiovascular or renal protection in heart disease (heart failure, post-myocardial infarction, high vascular risk) or kidney disease (diabetic nephropathy). Moreover, more complete RAS blockade is risky in conditions where blood pressure and renal perfusion are renin-dependent (renal failure and hypotension) and also in hypoaldosteronism (hyperkalemia). The European, French and US. health agencies have contraindicated combined RAS blockade because of its unfavorable risk-benefit balance, especially in patients with diabetes or renal failure.

Renal tubular dysgenesis is a severe disease characterized by the absence of differentiated proximal tubules, leading to fetal anuria and persistent oligohydramnios. The absence of amniotic fluid results in a series of malformations, including facial dysmorphia, limb deformation and also lung hypoplasia, leading to respiratory distress at birth. The disease is linked to mutations in the AGT, REN ACE andAGTR1 genes that compose the renin-angiotensin system (RAS). The absence of functional RAS leads to fetal and neonatal hypotension, renal hypoperfusion, and tubular dysgenesis. The use of cellular models expressing these mutations has advanced our understanding of the structure-function relationship of RAS proteins, notably by showing that defective misfolded proteins undergo either intracellular accumulation and retention, or rapid degradation. Moreover, these studies confirm that ACE has to be inserted in the plasma membrane to be active.

Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden.Project compares quantitatively outpatient drug prescriptions in France, Denmark, Norway and Sweden.Data were obtained from national databases; the unit of measurement was defined daily dose per 1000 inhabitants. The five most prescribed drug classes were compared in each country in 2009, then benzodiazepines and antibiotics from 2006 to 2012. A literature review was focused on the context of prescriptions for each country.In 2009, the five most prescribed drug classes in the four countries represented seven classes in total. France was not the biggest prescriber of drugs, but from 2006 to 2012 benzodiazepines and antibiotics were prescribed much more in France than in the other countries. The evolution of prescriptions was different for each country, and very stable in France.In 2009, France was not the biggest drugs consumer of all classes, but was characterized by high prescriptions in some classes.

Le diabète de type 2 est une pathologie chronique complexe associant une altération de sécrétion de l'insuline par le pancréas et une résistance à l'insuline au niveau des tissus périphériques, notamment au niveau du foie et du muscle squelettique. Son origine est multifactorielle, alliant des anomalies génétiques et environnementales, en particulier nutritionnelles. Un des mécanismes par lesquels les facteurs nutritionnels (comme les glucides et les lipides en excès) contribuent au développement du diabète et à son aggravation est la glucolipotoxicité. En effet, l'élévation de la glycémie et des lipides plasmatiques, ainsi que l'accumulation ectopique de lipides dans les tissus, participent au développement de l'insulinorésistance hépatique et musculaire et aux dysfonctions des cellules bêta, en partie via l'induction d'un stress métabolique, impliquant notamment le stress oxydant, le stress du réticulum endoplasmique (RE) et la perturbation de l'homéostasie calcique. Nous avons étudié les effets de la glucotoxicité et de la lipotoxicité dans les cellules bêta pancréatiques et les mécanismes impliqués. Nous nous sommes aussi intéressés à des traitements potentiellement protecteurs de la fonction bêta-pancréatique. Nous avons fait l'hypothèse que les effets bénéfiques de l'inhibition du système rénine-angiotensine sur l'incidence du diabète de type 2 chez l'homme étaient médiés par une action directe sur les cellules bêta. Nos résultats montrent que le glucose chronique à une dose élevée entraine une réduction de la sécrétion d'insuline des cellules bêta des îlots de Langerhans humains par une action conjointe sur le stress du RE, le stress oxydant et l'homéostasie calcique. L'inhibition du SRA a permis de restaurer cette fonction grâce notamment à une action inhibitrice sur la voie Phospholipase C-IP3-Calcium, This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in type 2 diabetes, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor t- AUCB (10 mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids and LDL cholesterol, and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the NO-synthase and cytochrome P450 epoxygenase inhibitors, L-NA and MSPPOH, on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis and inflammation, and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the enddiastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that she inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese type 2 diabetic mice

This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in type 2 diabetes, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor t- AUCB (10 mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids and LDL cholesterol, and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the NO-synthase and cytochrome P450 epoxygenase inhibitors, L-NA and MSPPOH, on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis and inflammation, and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the enddiastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that she inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese type 2 diabetic mice, Le diabète de type 2 est une pathologie chronique complexe associant une altération de sécrétion de l'insuline par le pancréas et une résistance à l'insuline au niveau des tissus périphériques, notamment au niveau du foie et du muscle squelettique. Son origine est multifactorielle, alliant des anomalies génétiques et environnementales, en particulier nutritionnelles. Un des mécanismes par lesquels les facteurs nutritionnels (comme les glucides et les lipides en excès) contribuent au développement du diabète et à son aggravation est la glucolipotoxicité. En effet, l'élévation de la glycémie et des lipides plasmatiques, ainsi que l'accumulation ectopique de lipides dans les tissus, participent au développement de l'insulinorésistance hépatique et musculaire et aux dysfonctions des cellules bêta, en partie via l'induction d'un stress métabolique, impliquant notamment le stress oxydant, le stress du réticulum endoplasmique (RE) et la perturbation de l'homéostasie calcique. Nous avons étudié les effets de la glucotoxicité et de la lipotoxicité dans les cellules bêta pancréatiques et les mécanismes impliqués. Nous nous sommes aussi intéressés à des traitements potentiellement protecteurs de la fonction bêta-pancréatique. Nous avons fait l'hypothèse que les effets bénéfiques de l'inhibition du système rénine-angiotensine sur l'incidence du diabète de type 2 chez l'homme étaient médiés par une action directe sur les cellules bêta. Nos résultats montrent que le glucose chronique à une dose élevée entraine une réduction de la sécrétion d'insuline des cellules bêta des îlots de Langerhans humains par une action conjointe sur le stress du RE, le stress oxydant et l'homéostasie calcique. L'inhibition du SRA a permis de restaurer cette fonction grâce notamment à une action inhibitrice sur la voie Phospholipase C-IP3-Calcium