PubMed Health⌕ Search

Biomedical subjects

Jean-Loup Bascands

Publications and source records attributed to Jean-Loup Bascands.

17 recordsLinked to original sources
PubMed2006

Predicting the clinical outcome of congenital unilateral ureteropelvic junction obstruction in newborn by urinary proteome analysis.

We analyzed urinary polypeptides from individuals with neonatal ureteropelvic junction (UPJ) obstruction to predict which individuals with this condition will evolve toward obstruction that needs surgical correction. We identified polypeptides that enabled diagnosis of the severity of obstruction and validated these biomarkers in urine collected in a prospective blinded study. Using these noninvasive biomarkers, we were able to predict, several months in advance and with 94% precision, the clinical evolution of neonates with UPJ obstruction.

Biomarkers↗
PubMed2006

Role of the kinin B1 receptor in insulin homeostasis and pancreatic islet function.

Kinins are potent vasoactive peptides generated in blood and tissues by the kallikrein serine proteases. Two distinct kinin receptors have been described, one constitutive (subtype B2) and one inducible (subtype B1), and many physiological functions have been attributed to these receptors, including glucose homeostasis and control of vascular permeability. In this study we show that mice lacking the kinin B1 receptor (B1-/- mice) have lower fasting plasma glucose concentrations but exhibit higher glycemia after feeding when compared to wild-type mice. B1-/- mice also present pancreas abnormalities, characterized by fewer pancreatic islets and lower insulin content, which leads to hypoinsulinemia and reduced insulin release after a glucose load. Nevertheless, an insulin tolerance test indicated higher sensitivity in B1-/- mice. In line with this phenotype, pancreatic vascular permeability was shown to be reduced in B1 receptor-ablated mice. The B1 agonist desArg9bradykinin injected intravenously can induce the release of insulin into serum, and this effect was not observed in the B1-/- mice or in isolated islets. Our data demonstrate the importance of the kinin B1 receptor in the control of pancreatic vascular homeostasis and insulin release, highlighting a new role for this receptor in the pathogenesis of diabetes and related diseases.

Animals↗
PubMed2005

Direct protein-protein interaction between PLCgamma1 and the bradykinin B2 receptor--importance of growth conditions.

Recently, we have described a novel protein-protein interaction between the G-protein coupled bradykinin B2 receptor and tyrosine phosphatase SHP-2 via an immunoreceptor tyrosine-based inhibition motif (ITIM) sequence located in the C-terminal part of the B2 receptor and the Src homology (SH2) domains of SHP-2. Here we show that phospholipase C (PLC)gamma1, another SH2 domain containing protein, can also interact with this ITIM sequence. Using surface plasmon resonance analysis, we observed that PLCgamma1 interacted with a peptide containing the phosphorylated form of the bradykinin B2 receptor ITIM sequence. In CHO cells expressing the wild-type B2 receptor, bradykinin-induced transient recruitment and activation of PLCgamma1. Interestingly, this interaction was only observed in quiescent and not in proliferating cells. Mutation of the key ITIM residue abolished this interaction with and activation of PLCgamma1. Finally we also identified bradykinin-induced PLCgamma1 recruitment and activation in primary culture renal mesangial cells.

Amino Acid Sequence↗
PubMed2005

Obstructive nephropathy: insights from genetically engineered animals.

Congenital obstructive nephropathy is the primary cause for end-stage renal disease (ESRD) in children. An increasingly used animal model of obstructive nephropathy is unilateral ureteral obstruction (UUO). This model mimics, in an accelerated manner, the different stages of obstructive nephropathy leading to tubulointerstitial fibrosis: cellular infiltration, tubular proliferation and apoptosis, epithelial-mesenchymal transition (EMT), (myo)fibroblast accumulation, increased extracellular matrix (ECM) deposition, and tubular atrophy. During the last decade genetically modified animals are increasingly used to study the development of obstructive nephropathy. Although the use of these animals (mainly knockouts) has highlighted some pitfalls of this approach (compensation by closely related gene products, absence of temporal knockouts) it has brought important information about the role of specific gene-products in the pathogenesis of obstructive nephropathy. Besides confirming the important pathologic role for angiotensin II (Ang II) and transforming growth factor-beta (TGF-beta) in obstructive nephropathy, these animals have shown the complexity of the development of tubulointerstitial fibrosis involving a large number of closely functionally related molecules. More interestingly, the use of these animals has led to the discovery of unexpected and contradictory roles (both potentially pro- and antifibrotic) for Ang II, for ECM degrading enzymes matrix metalloproteinase 9 (MMP-9) and tissue plasminogen activators (PAs), for plasminogen activator inhibitor 1 (PAI-1), and for the adhesion molecule osteopontin (OPN) in obstructive nephropathy. Further use of these animals, especially in combination with pharmacologic tools, should help to better identify potential antifibrotic strategies in obstructive nephropathy.

Animals↗
PubMed2004

The bradykinin B1 receptor contributes to the cardioprotective effects of AT1 blockade after experimental myocardial infarction.

OBJECTIVE: To investigate the role of the bradykinin B1 receptor (B1R) on the angiotensin receptor AT1 blockade-dependent cardioprotective effects, we studied the B1R regulation in wild-type rats treated with the AT1 antagonist, irbesartan (IRB), and also in transgenic rats with cardiac overexpression of the human AT1 (TGR-alphaMHCAT1) after induction of myocardial infarction (MI). In addition, we treated wild-type rats with IRB and/or the B1R antagonist, B9958, and determined the left ventricular (LV) function. METHODS: Untreated, IRB (50 mg/kg/day/p.o.), B9958 (0.1 mg/kg/48 h/s.c.), and IRB/B9958-treated Sprague-Dawley rats were submitted to a permanent occlusion of the left descending coronary artery. Six days and three weeks after induction of MI, the LV function was characterized by using a Millar-tip catheter. Myocardial AT1- and B1-mRNA expression were analyzed by RNase-protection assays, B1R protein density by immunohistochemistry. RESULTS: At both time points, LV function had improved by almost 50% after treatment with IRB but remained unchanged in TGR-alphaMHCAT1 after induction of MI compared to their untreated controls. The beneficial effect of IRB was reversed by co-treatment with B9958. The B1R antagonist treatment alone had no effect. A cross-talk between AT1 and B1R was also indicated by an up-regulation of B1R after treatment with IRB on protein and RNA level, while AT1 overexpression reduced B1R expression after induction of MI. CONCLUSION: These results indicate that the mechanisms of B1R regulation are influenced by the AT1 receptor. Thus, we are able to demonstrate for the first time that the B1R contributes to the cardio-beneficial effects of AT1 blockade.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2003

Decreased renal NO excretion and reduced glomerular tuft area in mice lacking the bradykinin B2 receptor.

Bradykinin B(2) receptor knockout mice (B(2)-/-) have been useful to study the role of bradykinin under pathological conditions. With the use of these mice, it was shown that bradykinin plays an important role in angiogenesis, heart failure, salt-induced hypertension, and kidney fibrosis. Data on the role of the bradykinin B(2) receptor under physiological conditions using these mice are controversial and scarce, because these mice have no typical phenotype. For this reason, we have studied, under physiological conditions, renal hemodynamics as well as a number of morphometric glomerular parameters of B(2)-/- mice on a homogenized genetic background and on mice bred in a pathogen-free environment. Backcrossed B(2)-/- mice had normal blood pressure and normal apparent renal hemodynamics and morphology. However, reduced renal nitrite excretion and glomerular cGMP content were found, which was associated with a reduced glomerular capillary surface area. These differences had, however, no detectable effects on renal hemodynamics. These differences between B(2)-/- and wild-type mice might become important under pathological conditions as shown by a number of studies using these bradykinin B(2) receptor knockout mice.

Animals↗
PubMed2003

[Bradykinin receptors: towards new pathophysiological roles].

In addition to being a pro-inflammatory mediator, bradykinin is now recognized as a neuromediator and regulator of several vascular and renal functions. New breakthroughs point to unusual and atypical signalling pathways for a G-protein coupled receptor that could explain the anti-proliferative and anti-fibrogenic effects of bradykinin. The availability of transgenic and knock out animal models for bradykinin receptors or bradykinin-synthesizing or -catabolic enzymes confirms these cardiac and renal protective roles for this peptide system. Bradykinin receptors are involved in the therapeutic action of angiotensin-1 converting enzyme inhibitors that are used in the treatment of arterial hypertension, heart failure and diabetes. Nevertheless, recent evidence highlights dissimilar mechanisms in the regulation and function of these receptors between the central nervous system and peripheral tissues. Therefore, the development of more specific bradykinin receptor agonists or antagonists devoid of central actions seems to evolve as a new therapeutic approach.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

The protective effect of angiotensin converting enzyme inhibition in experimental renal fibrosis in mice is not mediated by bradykinin B2 receptor activation.

Unilateral ureteral obstruction (UUO) is an animal model of accelerated renal tubulointerstitial fibrosis. We have recently shown, using this model, that mice lacking the bradykinin B2-receptor (B2(-/-)) were more susceptible than control animals to the development of tubulointerstitial fibrosis. Angiotensin converting enzyme (ACE) inhibition slows down UUO-induced renal fibrosis. Since ACE-inhibition increases bradykinin and decreases angiotensin II concentrations we have verified if bradykinin is involved in the antifibrotic effects of ACE-inhibition using the UUO-model and B2(-/-) mice. Surprisingly, although ACE-inhibition significantly reduced renal fibrosis, no difference was observed between the degree of tubulointerstitial fibrosis, macrophage infiltration and cell proliferation between ACE-inhibitor treated B2(+/+) and B2(-/-) mice suggesting the absence of a role of the B2-receptor in the antifibrotic effects of ACE-inhibition. This was confirmed at the level of bradykinin-induced activity of enzymes involved in the degradation of the extracellular matrix. However in both mouse strains, ACE-inhibitors were more efficient than AT1 receptor antagonists.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation.

Several experimental data report both mitogenic and antimitogenic effects of bradykinin (BK). To conciliate these apparent opposite effects, we hypothesized that, depending on cell context activation, BK could reduce the mitogenic effect of growth factors. Therefore, in the present study we assessed the existence of possible negative cross talk between BK and potential pathogenic growth factors in freshly isolated rat glomeruli (IG). Next, we determined whether this cross talk could be pharmacologically recruited during angiotensin-converting enzyme (ACE) inhibition in the diabetic rat. In IG from normal rats, BK, via activation of the B(2) kinin receptor (B(2)R), causes a transient stimulation of ERK1/2 phosphorylation, whereas it inhibits ERK1/2 phosphorylation induced by IGF-1, PDGF-BB, VEGF, or basic FGF. The reduction of growth factor-induced ERK1/2 phosphorylation is abolished by an inhibitor of tyrosine phosphatase. In glomeruli from diabetic rats, hyperglycemia increased the phosphorylation level of ERK-1/2 as well as oxidative stress. The reversal of these events by ACE inhibition is mediated via B(2)R activation. These observations are consistent with a potential therapeutic role of BK and B(2)R during glomerulosclerosis.

Animals↗
PubMed2002

A novel protein-protein interaction between a G protein-coupled receptor and the phosphatase SHP-2 is involved in bradykinin-induced inhibition of cell proliferation.

Mitogenic G protein-coupled receptor (GPCR) signaling has been extensively studied. In contrast, little is known about anti-mitogenic GPCR signaling. We show here that anti-mitogenic signaling of a GPCR, the bradykinin B2 receptor, involves a novel direct protein-protein interaction. The antiproliferative effect of bradykinin was accompanied by a transient increase in protein-tyrosine phosphatase activity. Using surface plasmon resonance analysis, we observed that an immunoreceptor tyrosine-based inhibitory motif (ITIM) located in the C-terminal part of the B2 receptor interacted specifically with the protein-tyrosine phosphatase SHP-2. The interaction was confirmed in primary culture renal mesangial cells by co-immunoprecipitation of a B2 receptor.SHP-2 complex. The extent of the interaction was transiently increased by stimulation with bradykinin, which was accompanied by an increase in specific SHP-2 phosphatase activity. Mutational analysis of the key ITIM residue confirmed that the B2 receptor ITIM sequence is required for interaction with SHP-2, SHP-2 activation, and the anti-mitogenic effect of bradykinin. Finally, in mesangial cells transfected with a dominant-negative form of SHP-2, bradykinin lost the ability to inhibit cell proliferation. These observations demonstrate that bradykinin inhibits cell proliferation by a novel mechanism involving a direct protein-protein interaction between a GPCR (the B2 receptor) and SHP-2.

Amino Acid Sequence↗
PubMed2002

Induction of functional bradykinin b(1)-receptors in normotensive rats and mice under chronic Angiotensin-converting enzyme inhibitor treatment.

BACKGROUND: The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B(1)- and B(2)-receptor expression, which are the molecular entities responsible for the biological effects of kinins. METHODS AND RESULTS: Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT(1)-receptor antagonist, and B(1)- and B(2)-receptor antagonists. Chronic ACE inhibition induced both renal and vascular B(1)-receptor expression, whereas B(2)-receptor expression was not modified. Furthermore, with B(1)-receptor antagonists, it was shown that B(1)-receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B(1)-receptors in all segments. ACE-inhibitor-induced B(1)-receptor induction involved homologous upregulation, because it was prevented by B(1)-receptor antagonist treatment. Finally, using B(2)-receptor knockout mice, we showed that ACE-inhibitor-induced B(1)-receptor expression was B(2)-receptor independent. CONCLUSIONS: This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B(1)-receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B(1)-receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.

Angiotensin Receptor Antagonists↗
PubMed2002

Inhibition of IGF-I-induced Erk 1 and 2 activation and mitogenesis in mesangial cells by bradykinin.

BACKGROUND: The beneficial effects of therapeutic angiotensin-converting enzyme (ACE) inhibitor treatment against the worsening of glomerulosclerosis during the course of diabetic nephropathy have been widely documented. ACE inhibitors inhibit both angiotensin II formation and bradykinin (BK) degradation, thereby reducing angiotensin II type 1 (AT1) receptor activity and favoring B2-kinin receptor (B2 receptor) activation. Since the involvement of growth factors such as insulin-like growth factor (IGF-I) has been implicated in the early steps of diabetic nephropathy, we investigated the effect of BK on Erk 1 and 2 activation and cell proliferation by IGF-I. METHODS: The activation of Erk 1 and 2 in mesangial cells (MCs) and isolated glomeruli (IG) was investigated by immunoprecipitation and Western blotting during activation of the IGF-I receptor in the presence or absence of BK and of protein kinase C (PKC), tyrosine-kinase and phosphatase selective inhibitors. Mesangial cell proliferation was assessed in vitro by cell counting. RESULTS: In untreated MCs and IG, when added separately, BK and IGF-I both activated Erk 1 and 2. In contrast, in MCs and IG pretreated with BK, the IGF-I-induced Erk 1 and 2 activation was dose-dependently reduced. The inhibitory effect of BK on IGF-I-induced activation of Erk 1 and 2 was completely abolished by addition of a B2 antagonist, by chelation of intracellular calcium and by tyrosine phosphatase inhibition. Additionally, BK reduced MC proliferation induced by IGF-I. CONCLUSIONS: A new inhibitory pathway of the early steps of IGF-I signaling by the B2 receptor is found both in cultured MCs and in IG, which involves a calcium-dependent tyrosine phosphatase activity. Recruitment of this mechanism may account for the beneficial effects of ACE inhibitor treatment on glomerulosclerosis associated with diabetic nephropathies.

Animals↗
PubMed2002

Induction of B1 receptors in streptozotocin diabetic rats: possible involvement in the control of hyperglycemia-induced glomerular Erk 1 and 2 phosphorylation.

We investigated the effects of a 3-week treatment with various combinations of angiotensin-converting enzyme inhibitor (ACEI) and B1 and B2 bradykinin receptor (B1R and B2R) antagonists (B1A and B2A) and AT1 receptor antagonist on ERK 1 and 2 phosphorylation in isolated glomeruli from streptozotocin-treated diabetic rats (STZ rats). Body weight, glycemia, and blood pressure were monitored. The rats were divided into nine groups: (1) control; and groups 2-9 were STZ treated with (3) insulin, (4) ACEI, (5) ACEI + B1A, (6) ACEI + B2A, (7) B2A, (8) B1A, (9) AT1 antagonist. ERK 1 and 2 phosphorylation and expression of B1R and B2R were assessed by Western blot analysis. ERK 1 and 2 phosphorylation was higher in STZ rats; this activation was normalized by insulin and reduced by ACEI but not by AT1 antagonist. The reduction of ERK 1 and 2 phosphorylation by the ACEI was reversed by B1A and B2A. The induction of B1R was confirmed by increased expression of mRNA and B1 receptor protein. Since ERK 1 and 2 phosphorylation is an early event in the induction of matrix secretion and hyperproliferation associated with diabetic nephropathy, activation of B1R and B2R appears to be a useful pharmacological target in the management of this pathology.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

B2 receptor activation reduces Erk1 and Erk2 phosphorylation induced by insulin-like growth factor-1, platelet-derived growth factor-BB, and high glucose in rat isolated glomeruli.

Several experimental data document an activation of the mitogen-activated protein kinases Erk1 and Erk2 by bradykinin (BK), an agonist of the kinin B2 receptor (B2R). In contrast, other reports showed an inhibitory modulation of mitogenesis by BK. Therefore, we explored in the isolated glomeruli the effect of B2R activation on the signaling of insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-BB (PDGF-BB), and high glucose (HG), three factors that are believed to be involved in the development of glomerulosclerosis via the phosphorylation of Erk1 and Erk2. We observed that the activation of B2R negatively modulates the phosphorylation of Erk1 and Erk2 induced by IGF-1, PDGF-BB, and HG in the glomerulus. These effects are consistent with the hypothesis of a protective role for BK in the kidney during development of glomerulosclerosis and renal pathologies associated with a hyperproliferative state.

Animals↗
PubMed2002

In vivo bradykinin B2 receptor activation reduces renal fibrosis.

Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of various fibrotic renal diseases both in humans and in animal models. Unilateral ureteral obstruction (UUO) is an animal model of accelerated renal tubulointerstitial fibrosis that is attenuated by ACE inhibition. Although ACE inhibitors increase bradykinin concentrations in addition to their effect on angiotensin II formation, the role of bradykinin in renal fibrosis has not been studied. We show here that genetic ablation (B2(-/-) mice) or pharmacological blockade of the bradykinin B2 receptor increases UUO-induced interstitial fibrosis in mice, whereas transgenic rats expressing increased endogenous bradykinin show reduced UUO-induced interstitial fibrosis. The increased interstitial fibrosis in B2(-/-) mice was accompanied by a decreased activity of plasminogen activators (PAs) and metalloproteinase-2 (MMP-2), enzymes involved in ECM degradation, suggesting that the protective effects of bradykinin involve activation of a B2 receptor/PA/MMP-2 cascade. This ability of bradykinin to increase PA activity was confirmed in primary culture proximal tubular cells. Thus, in both mice and rats, bradykinin B2 receptor activation reduces renal tubulointerstitial fibrosis in vivo, most likely by increasing ECM degradation.

Animals↗
PubMed2000

Bradykinin B(1) receptor-mediated changes in renal hemodynamics during endotoxin-induced inflammation.

Kinins have been shown to influence renal hemodynamics and function. Under physiologic conditions, most kinin effects involve bradykinin B(2) receptors, but bradykinin B(1) receptors are often induced during inflammation. The purpose of this study was to examine in vivo the effects of bradykinin B(1) receptor activation on renal hemodynamics under normal and inflammatory conditions. In anesthetized rats, activation of bradykinin B(1) receptors by arterial infusion of bradykinin B(1) receptor agonist des-Arg(9)-bradykinin reduced renal plasma flow and GFR. Prior administration (18 h) of lipopolysaccharide to induce inflammation resulted in a larger bradykinin B(1) receptor-induced reduction in renal plasma flow. Values of other parameters remained unchanged, thus resulting in an increased filtration fraction. The presence and the functionality of the bradykinin B(1) receptor at the level of glomerular afferent and efferent arterioles were studied by mRNA expression analysis and intracellular calcium ([Ca(2+)](i)) mobilization studies. Stimulation with des-Arg(9)-bradykinin of microdissected afferent arterioles from control and lipopolysaccharide-treated rats induced [Ca(2+)](i) mobilization without any significant difference in amplitude between control and lipopolysaccharidetreated rats. However, des-Arg(9)-bradykinin only induced [Ca(2+)](i) mobilization in efferent arterioles from lipopolysaccharide-treated rats. It is suggested that activation of bradykinin B(1) receptors located along the efferent arteriole may participate in the modification of renal hemodynamics in inflammatory states.

Animals↗