angiopoietin 2
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2022 ◽  
pp. ASN.2021060757
Author(s):  
Sherry Mansour ◽  
Pavan Bhatraju ◽  
Steven Coca ◽  
Wassim Obeid ◽  
Francis Wilson ◽  
...  

Background The mechanisms underlying long-term sequelae following acute kidney injury (AKI) remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for chronic kidney disease (CKD) and heart failure. Methods To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure, as well as the secondary outcome of all-cause mortality 3 months after discharge or later. Results Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [95% CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. Conclusions A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.


2021 ◽  
Author(s):  
Jiahao Liu ◽  
Viji Nair ◽  
Yi-yang Zhao ◽  
Dong-yuan Chang ◽  
Felix Eichinger ◽  
...  

Diabetes is the leading cause of chronic kidney disease. Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of diabetic kidney disease (DKD). In the Clinical Phenotyping and Resource Biobank study, an unbiased, machine learning approach identified a three-marker panel from plasma proteomics which, when added to standard clinical parameters, improved the prediction of outcome of end-stage kidney disease (ESKD) or 40% decline in baseline glomerular filtration rate (GFR) in a discovery DKD group (N=58) and was validated in an independent group (N=68) who also had kidney transcriptomic profiles available. Of the three markers, plasma angiopoietin 2 (ANGPT2) remained significantly associated with composite outcome in 210 Chinese Cohort Study of Chronic Kidney Disease participants with DKD. The glomerular transcriptional Angiopoietin/Tie (ANG-TIE) activation scores, derived from the expression of 154 literature-curated ANG-TIE signaling mediators, positively correlated with plasma ANGPT2 levels and outcome, explained by substantially higher TEK receptor expression in glomeruli and higher ANG-TIE activation scores in endothelial cells in DKD by single cell RNA sequencing. Our work suggests that activation of glomerular ANG-TIE signaling in the kidneys underlies the association of plasma ANGPT2 with disease progression, thereby providing potential targets to prevent DKD progression.


2021 ◽  
Vol 8 ◽  
Author(s):  
Bi Huang ◽  
Li Tian ◽  
Zhaoran Chen ◽  
Liang Zhang ◽  
Wenjun Su ◽  
...  

Biomarker-assisted diagnosis of acute aortic dissection (AAD) is important for initiation of treatment and improved survival. However, identification of biomarkers for AAD in blood is a challenging task. The present study aims to find the potential AAD biomarkers using a transcriptomic strategy. Arrays based genome-wide gene expression profiling were performed using ascending aortic tissues which were collected from AAD patients and healthy donors. The differentially expressed genes were validated using quantitative reverse transcriptase PCR (qRT-PCR) and western blot. The plasma levels of a potential biomarker, angiopoietin 2 (ANGPT2) were determined in case-control cohort (77 AAD patients and 82 healthy controls) by enzyme linked immunosorbent assay. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic power of ANGPT2 for AAD. Transcriptome data demonstrated that a total of 18 genes were significantly up-regulated and 28 genes were significantly down-regulated among AAD tissues (foldchange>3.0, p < 0.01). By bioinformatic analysis, we identified ANGPT2 as a candidate biomarker for blood-based detection of AAD. The qRT-PCR and protein expression demonstrated that ANGPT2 increased 2.4- and 4.2 folds, respectively in aortic tissue of AAD patients. Immunohistochemical staining demonstrated that ANGPT2 was markedly increased in intima of the aortic wall in AAD. Furthermore, ANGPT2 was significantly elevated in AAD patients as compared with controls (median 1625 vs. 383 pg/ml, p < 1E-6). ROC curve analysis showed that ANGPT2 was highly predictive of a diagnosis of type A AAD (area under curve 0.93, p < 1E-6). Sensitivity and specificity were 81 and 90%, respectively at the cutoff value of 833 pg/ml. In conclusion, ANGPT2 could be a promising biomarker for diagnosis of AAD; however, more studies are still needed to verify its specificity in diagnosing of AAD.


2021 ◽  
Author(s):  
Marije Kat ◽  
Ellie Karampini ◽  
Arie Johan Hoogendijk ◽  
Petra Bürgisser ◽  
Aat A. Mulder ◽  
...  

AbstractVon Willebrand factor (VWF) is a multimeric hemostatic protein primarily synthesized in endothelial cells (ECs). VWF is stored in endothelial storage organelles, the Weibel-Palade bodies (WPBs), whose biogenesis strongly depends on VWF anterograde trafficking and Golgi architecture. Elongated WPB morphology is correlated to longer VWF strings with better adhesive properties. We previously identified the SNARE SEC22B, which is involved in anterograde ER-to-Golgi transport, as a novel regulator of WPB elongation. To elucidate novel determinants of WPB morphology we explored endothelial SEC22B interaction partners in a mass spectrometrybased approach, identifying the Golgi SNARE Syntaxin 5 (STX5). We established STX5 knockdown in ECs using shRNA-dependent silencing and analyzed WPB and Golgi morphology, using confocal and electron microscopy. STX5-depleted ECs exhibited extensive Golgi fragmentation and decreased WPB length, which was associated with reduced intracellular VWF levels, and impaired stimulated VWF secretion. However, the secretion-incompetent organelles in shSTX5 cells maintained WPB markers such as Angiopoietin 2, P-selectin, Rab27A, and CD63. Taken together, our study has identified SNARE protein STX5 as a novel regulator of WPB biogenesis.


Author(s):  
Irfan Khan ◽  
Marcel O. Schmidt ◽  
Bhaskar Kallakury ◽  
Sidharth Jain ◽  
Shaunt Mehdikhani ◽  
...  

Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a–Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a -dependent senescent cells by administration of AP20187. Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen and brain tissues. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects.


2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Lucia Mendes Silva ◽  
Elaine Cristina Oliveira Silva ◽  
Rayane Martins Botelho ◽  
Liliane Patricia Gonçalves Tenorio ◽  
Aldilane Lays Xavier Marques ◽  
...  

Group B Streptococcus (GBS) infection during pregnancy is involved in maternal sepsis, chorioamnionitis, prematurity, fetal infection, neonatal sepsis, and neurodevelopmental alterations. The GBS-induced chorioamnionitis leads to a plethora of immune and trophoblast cells alterations that could influence endothelial cells to respond differently to angiogenic mediators and alter placental vascular structure and function in pregnant women. In this context, preventive measures are needed to reduce such dysfunctions. As such, we evaluated the effects of a non-lethal exposure to inactivated GBS on trophoblast cells and chorionic villi explants, and if the treatment with uvaol would mitigate these effects. The concentration of 106 CFU of GBS was chosen since it was unable to reduce the HTR-8/SVneo cell line nor term chorionic villi explant viability. Raman spectroscopy of trophoblast cells showed significant alterations in their biochemical signature, mostly reverted by uvaol. GBS exposure increased HTR-8/SVneo cells IL-1β and IFN-γ production, phagocytosis, oxidative stress, and decreased trophoblast cell migration. The Ea.hy926 endothelial cell line produced angiopoietin-2, CXCL-8, EGF, FGF-b, IL-6, PlGF, sPECAM-1, and VEGF in culture. When co-cultured in invasion assay with HTR-8/SVneo trophoblast cells, the co-culture had increased production of angiopoietin-2, CXCL-8, FGF-b, and VEGF, while reduced sPECAM-1 and IL-6. GBS exposure led to increased CXCL-8 and IL-6 production, both prevented by uvaol. Chorionic villi explants followed the same patterns of production when exposed to GBS and response to uvaol treatment as well. These findings demonstrate that, even a non-lethal concentration of GBS causes placental inflammation and oxidative stress, reduces trophoblast invasion of endothelial cells, and increases CXCL-8 and IL-6, key factors that participate in vascular dysregulation observed in several diseases. Furthermore, uvaol treatment prevented most of the GBS-provoked changes. Hence, uvaol could prevent the harmful effects of GBS infection for both the mother and the fetus.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jakob Wollborn ◽  
Lars O. Hassenzahl ◽  
Daniel Reker ◽  
Hans Felix Staehle ◽  
Anne Marie Omlor ◽  
...  

Abstract Background The concomitant occurrence of the symptoms intravascular hypovolemia, peripheral edema and hemodynamic instability is typically named Capillary Leak Syndrome (CLS) and often occurs in surgical critical ill patients. However, neither a unitary definition nor standardized diagnostic criteria exist so far. We aimed to investigate common characteristics of this phenomenon with a subsequent scoring system, determining whether CLS contributes to mortality. Methods We conducted this single-center, observational, multidisciplinary, prospective trial in two separately run surgical ICUs of a tertiary academic medical center. 200 surgical patients admitted to the ICU and 30 healthy volunteers were included. Patients were clinically diagnosed as CLS or No-CLS group (each N = 100) according to the grade of edema, intravascular hypovolemia, hemodynamic instability, and positive fluid balance by two independent attending physicians with > 10 years of experience in ICU. We performed daily measurements with non-invasive body impedance electrical analysis, ultrasound and analysis of serum biomarkers to generate objective diagnostic criteria. Receiver operating characteristics were used, while we developed machine learning models to increase diagnostic specifications for our scoring model. Results The 30-day mortility was increased among CLS patients (12 vs. 1%, P = 0.002), while showing higher SOFA-scores. Extracellular water was increased in patients with CLS with higher echogenicity of subcutaneous tissue [29(24–31) vs. 19(16–21), P < 0.001]. Biomarkers showed characteristic alterations, especially with an increased angiopoietin-2 concentration in CLS [9.9(6.2–17.3) vs. 3.7(2.6–5.6)ng/mL, P < 0.001]. We developed a score using seven parameters (echogenicity, SOFA-score, angiopoietin-2, syndecan-1, ICAM-1, lactate and interleukin-6). A Random Forest prediction model boosted its diagnostic characteristics (AUC 0.963, P < 0.001), while a two-parameter decision tree model showed good specifications (AUC 0.865). Conclusions Diagnosis of CLS in critically ill patients is feasible by objective, non-invasive parameters using the CLS-Score. A simplified two-parameter diagnostic approach can enhance clinical utility. CLS contributes to mortality and should, therefore, classified as an independent entity. Trial Registration: German Clinical Trials Registry (DRKS No. 00012713), Date of registration 10/05/2017, www.drks.de Graphical Abstract


2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Amira Isaac ◽  
Tarek Maged El Sakaty ◽  
Sarah Hamdan Hussein ◽  
Hany Samir Rasmy

Abstract Background HCV infection is a major health concern. Disease progression to fibrosis, cirrhosis, and HCC is aided by the persistence of inflammatory reactions and cellular damage. Moreover, angiogenesis was found to have a substantial pathogenic role in disease progression. Serum Angiopoietin-2 appears to be correlated with liver stiffness in chronic HCV and its elevation is linked to disease progression from chronic hepatitis to cirrhosis. The aim of this study was to evaluate the role of serum Angiopoietin-2 in the prediction of regression of fibrosis in chronic HCV patients receiving direct-acting antiviral agents. Forty Egyptian chronic HCV patients for whom direct-acting antiviral agent (DAA) therapy was planned were included. All patients underwent assessment twice, at baseline and at SVR12, for standard laboratory tests, measurement of fibrosis using FibroScan, FIB-4 and APRI scores, and Angiopoietin-2 level. Results Statistically significantly higher levels of baseline Ang-2 were detected with the progression of fibrosis stages with a p-value of <0.001. The best cutoff value of baseline Ang-2 in discrimination of liver cirrhosis (F4) from F0-F3 was > 630 pg/ml with 85.71% sensitivity and 84.85% specificity. A statistically significant decline of Ang-2 (from 464.3±237.2 pg/ml to 401.3±277.1 pg/ml) was noted after the achievement of SVR12 with a p-value < 0.001. Regression of liver fibrosis in this study is defined as a decrease of more than or equal to one stage in liver fibrosis. Lower baseline fibrosis stages and other non-invasive scoring systems (FIB-4 and APRI scores) were associated with regression of fibrosis following successful DAAs treatment. However, higher baseline Ang-2 levels were significantly associated with non-regression of fibrosis, and at a cutoff of >680 pg/ml, it might predict non-regression of fibrosis after successful eradication of HCV with DAAs with 93.33% sensitivity and 70% specificity. Conclusions Angiopoietin-2 can be a useful predictor of fibrosis regression in chronic HCV patients receiving direct-acting antiviral agents. Elevated baseline Angiopoietin-2 and advanced fibrosis stages may predict non-regression of liver fibrosis.


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