The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes

Parving, Hans‐Henrik; Lehnert, Hendrik; Brøchner‐Mortensen, Jens; Gomis, Ramón; Andersen, Steen; Arner, Peter

doi:10.1056/nejmoa011489

Cited by 2,916 publications

(1,798 citation statements)

References 26 publications

Supporting

Mentioning

1,651

Contrasting

Unclassified

Order By: Relevance

“…77 The RAAS is thought to have a central function in the pathogenesis of this disease, evidenced by numerous studies showing that RAAS blockade by ACEIs and AT 1 receptor blockers slows the progression of DN. [3][4][5][6] However, these treatments do not halt the progression of this disease. Thus, the underlying mechanisms for progression of DN continue even in patients treated with accepted therapies.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

“…This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease [3][4][5][6] and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

View full text Add to dashboard Cite

The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

show abstract

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

View full text Add to dashboard Cite

show abstract

“…[5][6][7] Nevertheless, the drug class that is best for one indication might not automatically be the first choice for another indication such as essential hypertension. Angiotensin-converting enzyme inhibitors (ACEIs) have a key role in the treatment of heart failure and nephropathy, but are equivalent to other antihypertensive classes in randomised trials.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Cheung

Lauder

et al. 2005

J Hum Hypertens

View full text Add to dashboard Cite

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VA-LUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P ¼ 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P ¼ 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, Po0.0000001). In conclusion, the reduction in newonset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.

show abstract

“…Les interactions entre système rénine-angiotensine et complications vasculaires du diabète constituent un autre exemple de l'implication du TGF-β. Les inhibiteurs de l'enzyme de conversion et les antagonistes de l'angiotensine II [19,20] ont un effet protecteur vis-à-vis des complications vasculaires du diabète, entre autres via une diminution de l'expression du TGF-β. De même, le déterminisme génétique d'expression de l'enzyme de conversion est un des facteurs reconnus de susceptibilité aux complications vasculaires du diabète [21].…”

Section: Angiotensine II Et Fibroseunclassified

Système rénine-angiotensine et remodelage vasculaire

Michel

2004

Med Sci (Paris)

View full text Add to dashboard Cite

Le système rénine-angiotensine (SRA) consiste en une cascade d'interactions biochimiques aboutissant à la production de l'angiotensine II, un peptide de huit acides aminés qui interagit avec ses cellules cibles via des récepteurs à sept domaines transmembranaires couplés à des phospholipases par l'intermédiaire de protéines G. Nous nous intéresserons ici aux cibles directes de la rénine et de l'angiotensine II dans le système vasculaire. Une autre action importante de l'angiotensine II est de stimuler la sécrétion d'aldostérone par la corticosurrénale (les effets de l'aldostérone sur le remodelage vasculaire ne seront toutefois pas abordés ici, car ils nécessi-tent qu'un article entier leur soit consacré). Compartimentation physiologique du système rénine-angiotensineLe système rénine-angiotensine a été décrit comme un système endocrine par H. Goldblatt en 1934 [1]. La rénine active est synthétisée et stockée par les cellules myoépithélioïdes de l'artériole afférente du glomérule rénal. Sa sécrétion est contrôlée par divers stimulus diminuant la concentration de calcium libre dans la cellule myoépithé-lioïde: stimulation β-adrénergique, baisse de la tension pariétale dans l'artériole et diminution de la réabsorption du sodium et du chlore par le cotransport Na-K-2Cl de la macula densa. Inversement, l'augmentation du NaCl dans la macula densa, de même que l'angiotensine II elle-même, freinent la sécrétion de rénine en augmentant la concentration de calcium libre dans les cellules myoépithélioïdes. La rénine active sécrétée diffuse dans les compartiments plasmatique, lymphatique et interstitiel, de même que son substrat, l'angiotensinogène, synthétisé et sécrété par le foie (il est également probable que de faibles quantités d'angiotensinogène soient directement synthétisées au niveau de la paroi artérielle). À l'opposé, les peptides dérivés de l'angiotensinogène (angiotensines I et II) n'agissent vraisemblablement que dans le compartiment dans lequel ils ont été produits. Un point important est que la rénine active, si elle diffuse librement dans le plasma, s'adsorbe dans les tissus, en particulier dans la paroi artérielle. Dans le compartiment interstitiel, les résidus mannose-6 phosphate retiennent la rénine par des liaisons électrostatiques de faible affinité [2], > Le système rénine-angiotensine, l'un des principaux complexes de régulation de la pression sanguine, est distribué entre le sang circulant et l'espace péricellulaire de l'interstium tissulaire. Il participe en physiologie et en pathologie de la régulation de la vasomotricité et du remodelage tissulaire dans le système cardiovasculaire. Dans le cadre de ces effets, le système rénine-angiotensine tissulaire agit sur les cellules musculaires lisses vasculaires et les fibroblastes, tandis que le système rénine-angiotensine plasmatique a pour cibles les cellules endothéliales et les leucocytes circulants. L'angiotensine II, peptide actif du système, déclenche différentes voies de signalisation aboutissant à une réponse fonctionnelle immédiate (hypertens...

show abstract

The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes

Abstract: Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

Cited by 2,916 publications

References 26 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Système rénine-angiotensine et remodelage vasculaire

Contact Info

Product

Resources

About