The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy

Zeeuw, Dick de; Coll, Blai; Andress, Dennis L.; Brennan, John J.; Tang, Hui; Houser, Mark T.; Correa‐Rotter, Ricardo; Kohan, Donald E.; Heerspink, Hiddo J.L.; Makino, Hírofumi; Perkovic, Vlado; Pritchett, Yili; Remuzzi, Giuseppe; Tobe, Sheldon W.; Toto, Robert D.; Viberti, Giancarlo; Parving, Hans Henrik

doi:10.1681/asn.2013080830

Cited by 224 publications

(222 citation statements)

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“…Both the in vivo data as well as the mechanistic studies in vitro show that atrasentan is capable of reducing heparanase expression in the presence of a diabetic milieu. This study provides a new mechanism of action for ongoing clinical studies with ET A receptor blockers in diabetic nephropathy, where similar strong reductions in proteinuria were observed in the presence of only minor hemodynamic effects (11).…”

Section: Discussionmentioning

confidence: 57%

“…Because actual loss of renal function is a late indicator of disease, albuminuria has been put forward as a sensitive surrogate marker for ongoing renal injury in diabetic nephropathy. In this respect ET A receptor blockers seem to have a striking antiproteinuric effect that cannot be fully explained by reduced blood pressure (11).…”

Section: Atrasentan Reduces Albuminuria By Restoring the Glomerular Ementioning

confidence: 96%

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Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

et al. 2016

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Atrasentan, a selective endothelin A receptor antagonist, has been shown to reduce albuminuria in type 2 diabetes. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested the potential of atrasentan to stabilize the endothelial glycocalyx in diabetic apolipoprotein E (apoE)-deficient mice in relation to its antialbuminuric effects. Treatment with atrasentan (7.5 mg/kg/day) for 4 weeks reduced urinary albumin-tocreatinine ratios by 26.0 6 6.5% (P < 0.01) in apoE knockout (KO) mice with streptozotocin-induced diabetes consuming an atherogenic diet, without changes in gross glomerular morphology, systemic blood pressure, and blood glucose concentration. Endothelial cationic ferritin surface coverage, investigated using large-scale digital transmission electron microscopy, revealed that atrasentan treatment increases glycocalyx coverage in diabetic apoE KO mice from 40.7 6 3.2% to 81.0 6 12.5% (P < 0.05). This restoration is accompanied by increased renal nitric oxide concentrations, reduced expression of glomerular heparanase, and a marked shift in the balance of M1 and M2 glomerular macrophages. In vitro experiments with endothelial cells exposed to laminar flow and cocultured with pericytes confirmed that atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness in the presence of a diabetic milieu. Together these data point toward a role for the restoration of endothelial function and tissue homeostasis through the antialbuminuric effects of atrasentan, and they provide a mechanistic explanation for the clinical observations of reduced albuminuria with atrasentan in diabetic nephropathy.End-stage renal disease is inevitable in a majority of patients with diabetic nephropathy (1), despite optimal blood pressure treatment using drugs that interfere with the reninangiotensin system. Therefore there is a great need for additional strategies to slow the progression of chronic kidney disease in patients with diabetic nephropathy. One such strategy involves interaction with the endothelin (ET) system. Numerous studies involving experimental animal models have implicated ET in the pathogenesis of diabetic nephropathy (2). Moreover, clinical studies show promise for ET receptor antagonists in the treatment of diabetic nephropathy (3-6). This is particularly true for selective ET A receptor blockers; ET A receptor signaling seems to be involved in key renal pathophysiological processes such as the inflammatory response of renal epithelium to albumin (7), whereas stimulation of the associated concomitant ET B receptor can restore endothelial dysfunction by inducing endothelial nitric oxide (NO) production (8-10). Because actual loss of renal function is a late indicator of disease, albuminuria has been put forward as a sensitive surrogate marker for ongoing renal injury in diabetic nephropathy. In this respect ET A receptor blockers seem to have a striking

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Section: Discussionmentioning

confidence: 57%

Section: Atrasentan Reduces Albuminuria By Restoring the Glomerular Ementioning

confidence: 96%

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

et al. 2016

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“…Moreover, certain patient populations may be more prone to the adverse effects of ET blockade than others. 16 In the related clinical study, de Zeeuw et al 17 conducted a multicenter, multinational trial that examined the efficacy (reduction of albuminuria) and the adverse effect profile of atrasentan added to renin-angiotensin system inhibitor therapy. It is an extension of a previous dose-response study conducted by Kohan et al 13 in which addition of atrasentan to reninangiotensin system inhibition decreased albuminuria without increasing edema.…”

mentioning

confidence: 99%

Endothelin Antagonists in Diabetic Nephropathy

Chandrashekar¹,

Juncos

2014

Journal of the American Society of Nephrology

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The pivotal discovery of endothelin (ET) by Yanagisawa and colleagues 1 in 1988 generated wide interest in this peptide, as evidenced by the nearly 27,000 articles published to date that have examined its role in biology. ET is now recognized as essential to the function of various organs and metabolic processes. 2 The ET family consists of three 21-amino acid peptides-ET-1 (ubiquitous and most biologically active), ET-2, and ET-3-that exert their actions via two receptor subtypes: ET A and ET B 2 . Activation of these receptors usually, but not always, incites opposing actions; an additional consideration is that the ET B receptor also acts as a clearance receptor. 3 Consequently, the effects of ET can vary among different organs depending on the amount being formed and on the receptor subtypes present. For instance, in the cardiovascular system ET induces vasoconstriction and growth via ET A receptors and vasodilation and growth inhibition via ET B receptors. 1,3 The net effect results in an increase in systemic vascular resistance and BP. This potentially injurious effect is augmented by ET's ability to stimulate growth factors and cytokines, which induce neutrophil adhesion, platelet aggregation, and formation of extracellular matrix protein. 3 Together, these actions can precipitate a vicious cycle that accelerates hypertension and atherosclerosisinduced vascular disease. 3 Despite its importance in the cardiovascular system, ET plays an even larger role in regulating renal function and injury. This is because the kidneys are exquisitely sensitive to ET-1 (up to 10-fold more than are other organs 4 ) and because the components of the ET system are widely distributed throughout the kidney; ET-1 is present in the renal microvasculature, in all types of glomerular cells, and in the tubules (the renal medulla contains the highest ET-1 levels in the body 5 ). Thus, it is no surprise that ET-1 has such a key role in regulating renal hemodynamics, salt and water homeostasis, and acid-base balance 6 and in modulating cell proliferation, extracellular matrix accumulation, inflammation, and fibrosis. 7 Consequently, any abnormality in the intrarenal ET system may result in renal dysfunction (e.g., salt sensitivity) and/or injury. Indeed, ET may participate in the progression of renal injury during obesity, hypertension, and diabetes. 7 Because most of the deleterious effects of ET-1 appear to be mediated through the ET A receptors, this receptor has become an attractive therapeutic target in various forms of cardiovascular and renal diseases, such as diabetes. 3 Diabetic nephropathy is an attractive target for ET-1 blockade because several lines of evidence implicate ET in this disease. First, the synthesis and/or effects of ET-1 are increased in response to hyperglycemia, hypertensive glomerular injury, and insulin, 8 which results in increased renal expression and systemic circulatory levels of ET-1 in experimental and clinical diabetes. 9,10 Second, abnormalities in the ET system are present in the renal areas tar...

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“…Fluid retention was thought to be mediated mainly via ET-B receptor and atrasentan showed less of these side effects in animal models [42,43]. 211 participants were randomized to receive atrasentan 0.75 mg/day, 1.25 mg/day, or placebo and followed for 12 weeks.…”

Section: Therapiesmentioning

confidence: 99%

Diabetic nephropathy: newer therapeutic perspectives

Keri

Samji

Blumenthal

2018

Journal of Community Hospital Internal Medicine Perspectives

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Diabetic nephropathy (DN is a dreaded consequence of diabetes mellitus, accounting for about 40% of end-stage renal disease (ESRD). It is responsible for significant morbidity and mortality, both directly by causing ESRD and indirectly by increasing cardiovascular risk. Extensive research in this field has thrown light on multiple pathways that can be pharmacologically targeted, to control or reverse the process of DN. Glomerulocentric approach of DN still continues to produce favourable results as evidenced by the recent data on SGLT-2 (sodium glucose co-transporter type 2) inhibitors. Beyond the glomerular mechanisms, numerous novel pathways have been discovered in the last decade. Some of these pathways target inflammatory and oxidative damage, while the others target more specific mechanisms such as AGE-RAGE (advanced glycation end products-receptors for advanced glycation end products), ASK (apoptotic signal-regulating kinase), and endothelin-associated pathways. As a result of the research, a handful of clinically relevant drugs have made it to the human trials which have been elucidated in the following review, bearing in the mind that there are many more to come over the next few years. Ongoing research is expected to inform the clinicians regarding the use of the newer drugs in DN.Abbreviations: USFDA: Unites States Food and Drug Administration; SGLT-2: Sodium glucose transporter type 2; GLP-1: Glucagon-like peptide-1; DDP-4: Dipeptidyl peptidase-4; UACR: urinary albumin creatinine ratio; eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; DN: Diabetic nephropathy; TGF: Tubuloglomerular feedback; RAAS: Renin angiotensin aldosterone system; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; RCT: Randomized controlled trial; AGE-RAGE: Advanced glycation end products-receptors for advanced glycation end products; ASK-1: Apoptotic signal-regulating kinase-1; Nrf-2: Nuclear 1 factor [erythroid derived-2]-related factor 2; ml/min/1.73m2: Millilitre/minute/1.73 square meters of body surface area; ~: Approximately.

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The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy

Cited by 224 publications

References 17 publications

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

Endothelin Antagonists in Diabetic Nephropathy

Diabetic nephropathy: newer therapeutic perspectives

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