Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia

Wewers, Theresa M.; Schulz, Annika; Nolte, Ingo; Pavenstädt, Hermann; Brand, Marcus; Marco, Giovana Seno Di

doi:10.1681/asn.2020111579

Cited by 11 publications

(12 citation statements)

References 81 publications

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“…Higher sFlt-1 levels were also independently associated with incident heart failure or cardiovascular mortality in heart failure patients [23]. Moreover, elevated circulating sFlt-1 levels can cause glomerular endothelial cell damage in a series of kidney diseases, as the kidney possesses a highly organized vasculature and specialized endothelial cells [24]. Elevated sFlt-1 in MHT may suggest its role in helping diagnosis and evaluation of the severity of hypertensive organ damage.…”

Section: Discussionmentioning

confidence: 98%

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension

Ma,

Wang,

Jiang

et al. 2023

Journal of Hypertension

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Background and objectives: Malignant hypertension (MHT) characterized by acute hypertension with retinopathy or multiorgan damage, is a severe form of hypertensive emergency and associated with target organ involvement and poor kidney outcome. However, the underlying mechanisms are unclear. Methods: Eighty-four patients with acute severe hypertension from the Nephrology Department and Emergency Department in a single center during January 2016 and December 2017 were prospectively enrolled and divided into MHT (n = 48) and non-MHT (n = 36) subgroups according to target organ evaluation. Forty healthy controls were recruited. Serum soluble Fms-like tyrosine kinase-1 (sFlt-1) levels and plasma ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity were examined at baseline and 12-month follow-up. Renal endpoints were defined as a significant decrease in the estimated glomerular filtration rate (eGFR) of more than 40% or the occurrence of end-stage renal disease. Results: Serum sFlt-1 levels were persistently elevated in MHT. Baseline serum sFLT-1 levels were correlated with plasma ADAMTS13 activity and markers of target organ damage. Plasma ADAMTS13 activity was reduced in both MHT and non-MHT patients and recovered to the normal range at 12-month follow-up. During an average follow-up time of 53 ± 13 months, the restoration of reduced ADAMTS13 activity was correlated with the improvement of kidney function and independently reduced the risk of renal endpoints. Conclusions: Abnormal angiogenesis and endothelial damage are involved in the pathophysiology of hypertensive emergency. Evaluation of ADAMTS13 and sFlt-1 may help in the diagnosis and assessment of MHT. Recovery of ADAMTS13 predicts better renal outcome in patients with hypertensive emergencies.

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Section: Discussionmentioning

confidence: 98%

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension

Ma,

Wang,

Jiang

et al. 2023

Journal of Hypertension

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“…(C) Tissue of human preeclampsia decidual vasculopathy with fibrinoid necrosis are shown. (D) Inadequate remodelling by the cytotrophoblast invasion of spiral arteries reducing blood flow causing placental ischemia (PLA‐ISC) 12 , 13 promoting the secretion of sFlt‐1, 16 VEGF 20 and PIGF. 18 This environment promotes deregulation between e Hsp‐60, e Hsp‐70 and e Hsp‐27 (Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…14 During the second stage of this abnormal placentation, there is a proangiogenic and antiangiogenic imbalance, 15,16 including soluble Fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). [17][18][19][20] The decrease in these proteins in plasma is correlated with the severity of PE and with the development of adverse pregnancy outcomes [21][22][23] attributed to an increase in pro-inflammatory cytokines. 24,25 These serum markers and their indices (sFlt-1/PIGF ratio) are only used in prediction models later on in pregnancy.…”

Section: Introductionmentioning

confidence: 99%

First‐trimester plasma extracellular heat shock proteins levels and risk of preeclampsia

Robellada-Zárate

Luna-Palacios

Caballero

et al. 2023

J Cellular Molecular Medi

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Preeclampsia (PE) occurs annually in 8% of pregnancies. Patients without risk factors represent 10% of these. There are currently no first‐trimester biochemical markers that accurately predict PE. An increase in serum 60‐ and 70‐KDa extracellular heat shock proteins (eHsp) has been shown in patients who developed PE at 34 weeks. We sought to determine whether there is a relationship between first‐trimester eHsp and the development of PE. This was a prospective cohort study performed at a third level hospital in Mexico City from 2019 to 2020. eHsp levels were measured during the first‐trimester ultrasound in singleton pregnancies with no comorbidities. First‐trimester eHsp levels and biochemical parameters of organ dysfunction were compared between patients who developed preeclampsia and those who did not. All statistical analyses and model of correlation (r) between eHsp and clinical parameter were performed using bootstrapping R‐software. p‐values <0.05 were considered significant. The final analysis included 41 patients. PE occurred in 11 cases. eHsp‐60 and eHsp−70 were significantly higher at 12 weeks in patients who developed PE (p = 0.001), while eHsp‐27 was significantly lower (p = 0.004). Significant differences in first‐trimester eHsp concentration suggest that these are possible early biomarkers useful for the prediction of PE.

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“…Excess sFlt-1 is associated with endothelial dysfunction in heart failure, sepsis, preeclampsia, chronic kidney disease, kidney transplantation, and many other diseases, including COVID-19 infection [ 13 , 14 , 15 , 16 ]. Interestingly, the damage to the eGC was suggested to be the leading cause of endothelial dysfunction in various cardiovascular, inflammatory, and kidney diseases [ 12 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1

Schulz

Drost

Hesse

et al. 2023

IJMS

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Soluble fms-like tyrosine kinase-1 (sFlt-1) is a secreted protein that binds heparan sulfate expressed on the endothelial glycocalyx (eGC). In this paper we analyze how excess sFlt-1 causes conformational changes in the eGC, leading to monocyte adhesion, a key event triggering vascular dysfunction. In vitro exposure of primary human umbilical vein endothelial cells to excess sFlt-1 decreased eGC height and increased stiffness as determined by atomic force microscopy (AFM). Yet, structural loss of the eGC components was not observed, as indicated by Ulex europaeus agglutinin I and wheat germ agglutinin staining. Moreover, the conformation observed under excess sFlt-1, a collapsed eGC, is flat and stiff with unchanged coverage and sustained content. Functionally, this conformation increased the endothelial adhesiveness to THP-1 monocytes by about 35%. Heparin blocked all these effects, but the vascular endothelial growth factor did not. In vivo administration of sFlt-1 in mice also resulted in the collapse of the eGC in isolated aorta analyzed ex vivo by AFM. Our findings show that excess sFlt-1 causes the collapse of the eGC and favors leukocyte adhesion. This study provides an additional mechanism of action by which sFlt-1 may cause endothelial dysfunction and injury.

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Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia

Cited by 11 publications

References 81 publications

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension

First‐trimester plasma extracellular heat shock proteins levels and risk of preeclampsia

The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1

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