Roles of Angiopoietins in Kidney Development and Disease

Woolf, Adrian S.; Gnudi, Luigi; Long, David A.

doi:10.1681/asn.2008020243

Cited by 115 publications

(100 citation statements)

References 69 publications

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“…Interestingly, VEGFR1 is not only expressed on endothelial cells but also macrophages (39); therefore, the reduction in mRNA levels of this gene could reflect the overall decrease in renal inflammatory cell number in animals administered angiostatin before remnant kidney operation. We also investigated mRNA levels of the angiopoietins, which are important in the remodeling of established blood vessels and have also been implicated in several animal models of kidney disease (47). We observed no alteration in either angiopoietin-1 or angiopoietin-2 mRNA in animals treated with angiostatin, but there was a significant decrease in the receptor Tie-2.…”

Section: Discussionmentioning

confidence: 86%

Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism

Mu¹,

Long²,

Ouyang³

et al. 2009

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 86%

Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism

Mu¹,

Long²,

Ouyang³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…In particular, no treatment-related hypertension, hemorrhage, arterial thromboembolic events, or proteinuria were documented. Apart from the caveat of cross-trial comparisons, a mechanistic explanation of selective inhibition of Ang2 without Ang1 inhibition may account for the lack of proteinuria seen with nesvacumab (29)(30)(31), unlike the proteinuria grade ! 3 reported with the Ang1/Ang2 inhibitors trebananib and AMG780 (25,26), Except for one patient with vena cava thrombosis, occurring in the context of progressive retroperitoneal disease, there were no other thrombotic events.…”

Section: Discussionmentioning

confidence: 99%

A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors

Papadopoulos

Kelley

Tolcher

et al. 2016

Clinical Cancer Research

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Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in a-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D.

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“…[22][23][24] Angiopoietin-1 (Angpt1) and Angpt2 are ligands of the Tie-2 receptor, a family of growth factors specific for the vascular endothelium identified after discovery of vascular endothelial growth factor-A (VEGF-A). [25][26][27][28] In addition to angiogenesis, Angpt2 is an important regulator in numerous pathophysiologic processes, including inflammation. 29 Of note, circulating Angpt2 levels are correlated with systemic markers of microinflammation in patients with CKD.…”

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confidence: 99%

Angiopoietin-2–Induced Arterial Stiffness in CKD

Chang

Chiang

Chou

et al. 2014

Journal of the American Society of Nephrology

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The mechanism of vascular calcification in CKD is not understood fully, but may involve collagen deposition in the arterial wall upon osteo/chondrocytic transformation of vascular smooth muscle cells (VSMCs). Increased levels of circulating angiopoietin-2 correlate with markers of CKD progression and angiopoietin-2 regulate inflammatory responses, including intercellular and vascular adhesion and recruitment of VSMCs. Here, we investigate the potential role of angiopoietin-2 in the pathogenesis of arterial stiffness associated with CKD. In a cohort of 416 patients with CKD, the plasma level of angiopoietin-2 correlated independently with the severity of arterial stiffness assessed by pulse wave velocity. In mice subjected to 5/6 subtotal nephrectomy or unilateral ureteral obstruction, plasma levels of angiopoietin-2 also increased. Angiopoietin-2 expression markedly increased in tubular epithelial cells of fibrotic kidneys but decreased in other tissues, including aorta and lung, after 5/6 subtotal nephrectomy. Expression of collagen and profibrotic genes in aortic VSMCs increased in mice after 5/6 subtotal nephrectomy and in mice producing human angiopoietin-2. Angiopoietin-2 stimulated endothelial expression of chemokines and adhesion molecules for monocytes, increased Ly6C low macrophages in aorta, and increased the expression of the profibrotic cytokine TGF-b1 in aortic endothelial cells and Ly6C low macrophages. Angiopoietin-2 blockade attenuated expression of monocyte chemokines, profibrotic cytokines, and collagen in aorta of mice after 5/6 subtotal nephrectomy. This study identifies angiopoietin-2 as a link between kidney fibrosis and arterial stiffness. Targeting angiopoietin-2 to attenuate inflammation and collagen expression may provide a novel therapy for cardiovascular disease in CKD. 25: 119825: -120925: , 201425: . doi: 10.1681 Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with CKD. [1][2][3][4] Arteriosclerosis characterized by arterial stiffness is the major vascular complication. 5,6 The independent predictive value of arterial stiffness for CVD has been well demonstrated in different populations. 7,8 Although arterial stiffness is a hallmark of the aging process, many other factors such as endothelial dysfunction, local or systemic inflammation, and genetic factors are also implicated in the pathogenesis of arterial stiffness. [9][10][11] Arterial stiffness in patients with CKD is characterized by arterial intima-media hypertrophy resulting from alterations of the intrinsic properties of the arterial wall. 3,12 Increased arterial stiffness is observed in the early stages of CKD. 6,9 Arterial stiffness is accelerated in patients with CKD compared with age-, sex-, and pressure-matched controls, suggesting unique CKD-related factors leading to such a complication. 6,9,12 Traditional risk factors in patients with CKD, such as hypertension, diabetes, and hyperlipidemia, account for the increased CVD morbidity and mortality in part; however, actual m...

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Roles of Angiopoietins in Kidney Development and Disease

Cited by 115 publications

References 69 publications

Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism

Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism

A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors

Angiopoietin-2–Induced Arterial Stiffness in CKD

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