Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells

Collino, Federica; Bussolati, Benedetta; Gerbaudo, Elisa; Marozio, Luca; Pelissetto, Simona; Benedetto, Chiara; Camussi, Giovanni

doi:10.1152/ajprenal.00442.2007

Cited by 130 publications

(131 citation statements)

References 49 publications

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“…Moreover, WT sFlt-1 mice treated with ET-1 develop renal phenotypes similar to eNOS 2/2 sFlt-1 mice, evidenced by more severe albuminuria, decreased CCr, severe endotheliosis, and foot process effacement (Supplemental Figures S1 and S2). Our results are consistent with studies showing the association of ET-1 with pre-eclampsia [17][18][19] and with a recent study showing that sFlt-1 increases ET-1 expression in glomerular endothelial cells, 26 that ET-1 binds to its receptor in podocytes and causes nephrin shedding and proteinuria, and that an ET A receptor antagonist N-acetyl-[D-TRP 16 ]-ET1 fragment 16-21 abolishes these serial effects. 26 Taken together, our results indicate that the activated ET system is responsible for pre-eclampsia-like phenotypes observed in WT sFlt-1 and eNOS 2/2 sFlt-1 mice.…”

Section: Discussionsupporting

confidence: 93%

“…Our results are consistent with studies showing the association of ET-1 with pre-eclampsia [17][18][19] and with a recent study showing that sFlt-1 increases ET-1 expression in glomerular endothelial cells, 26 that ET-1 binds to its receptor in podocytes and causes nephrin shedding and proteinuria, and that an ET A receptor antagonist N-acetyl-[D-TRP 16 ]-ET1 fragment 16-21 abolishes these serial effects. 26 Taken together, our results indicate that the activated ET system is responsible for pre-eclampsia-like phenotypes observed in WT sFlt-1 and eNOS 2/2 sFlt-1 mice. Because ambrisentan decreases the increase in BP by sFlt-1, it cannot be ruled out that the enhanced effect of sFlt-1 on albuminuria observed in the eNOS 2/2 mice could, in part, be due to their higher BP.…”

Section: Discussionsupporting

confidence: 93%

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eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

Hagaman

Kim

et al. 2012

Journal of the American Society of Nephrology

109

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Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467674 versus 174623 mg/d), lower creatinine clearance (126629 versus 452663 ml/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET A receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ET A receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin system. Pre-eclampsia is a pregnancy-related disease characterized by high BP and proteinuria, and affects 3%-5% of all pregnancies. 1,2 Although the etiology of pre-eclampsia is not fully understood, it is widely accepted that placental hypoxia/ischemia increases the production by the placenta of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin, and likely other factors. 1 Increased sFlt-1 is recognized as one of the most important causal factors for maternal symptoms of pre-eclampsia. 1 sFlt-1 is a splice variant of vascular endothelial growth factor (VEGF) receptor-1 that lacks the cytoplasmic and transmembrane domains, but retains the ligandbinding domain. sFlt-1 decreases the chance of VEGF binding to its signaling receptor, and reduces the phosphorylation of Ser 1177 of endothelial nitric oxide synthase (eNOS) by VEGF and the activity of eNOS. 3 Plasma concentration of sFlt-1 is

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

Hagaman

Kim

et al. 2012

Journal of the American Society of Nephrology

109

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“…24 VEGF blockade induced ET-1 release from cultured glomerular endothelial cells, and the conditioned medium thus obtained triggered nephrin loss from podocytes. Conditioned medium obtained from cells incubated with PE sera induced a similar effect, which could be reversed by ET-1 receptor antagonist.…”

Section: Discussionmentioning

confidence: 87%

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

et al. 2011

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Placental overproduction of anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) has a key role in the development of preeclampsia (PE). Circulating endothelin-1 (ET-1) levels are also elevated in PE. In this study, we investigated the correlation between ET-1 and sFlt-1, placental growth factor (PlGF), sEng levels during uncomplicated normotensive pregnancy and PE. A total of 218 pregnant primigravid women were enrolled: 110 with PE and 108 uncomplicated normotensive pregnancies. PE was defined as new onset of elevated blood pressure (BP) 4140/90 mm Hg and X2 þ proteinuria on two occasions after 20 weeks of gestation in previously normotensive pregnant women. Circulating ET-1, sFlt-1, sEng and PlGF levels were estimated using enzyme immunoassays, and correlation between variables was ascertained. Women with PE showed higher levels of sFlt-1 (41.5 ± 15.7 vs 6.15 ± 3.4 ng ml -1 , Po0.001), sEng (84.9 ± 38.8 vs 13.2 ± 6.3 ng ml -1 , Po0.001), ET-1 (1.52 ± 0.55 vs 0.88±0.35 pg ml -1 , Po0.001) and sFlt-1:PlGF ratio (591.1±468.4 vs 18.3±2.1, Po0.001); and lower levels of PlGF (96.3 ± 47.2 vs 497.6 ± 328.2pg ml -1 , Po0.001). BP levels showed an independent relationship with sFlt-1:PlGF ratio in normotensive pregnant women and with sFlt-1:PlGF ratio and ET-1 in PE. sFlt-1 and sFlt-1:PlGF ratio correlated with proteinuria. ET-1 correlated significantly with sFlt-1, sEng and sFlt-1:PlGF ratio in PE. Our results show an association between elevation of sFlt-1 and sEng and ET-1 in the maternal circulation in PE, and strengthen the possibility that ET-1 may be a mediator in genesis of PE syndrome secondary to anti-angiogenic factors released by the placenta.

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“…40 Quantitative real-time PCR was performed on total RNA extracted from cells used to produce MVs and from an MV preparation different from those used for microarray analysis. Cell cDNA was used to evaluate primers efficiency.…”

Section: Quantitative Real Time Pcrmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury

Bruno¹,

Grange²,

Deregibus³

et al. 2009

Journal of the American Society of Nephrology

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1,157

1,173

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Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI).The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44-and ␤1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.

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Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells

Cited by 130 publications

References 49 publications

eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury

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