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Although the Common Agricultural Policy of the European Union has broadened its objectives to integrate social issues, several hard-to-reach groups of farmers and workers continue to be ignored by advisory services and associated policies. Connecting with these groups has a strong potential to increase the economic and social cohesion of European agricultures. We interviewed over 1,000 farmers across Europe and identified features of these groups that are often overlooked by advisory services. We critically reflected on the social cohorts omitted from advisory services and how they could be better reached; they include farm labourers, new entrants or ‘career changers’, and later adopters. We clarify the different types of advisors in the advisory landscape, distinguishing between those who are linked to or independent from sales of inputs or technologies. We make concrete recommendations about how to engage advisors with hard-to-reach groups, with approaches suited to different national contexts of Agricultural Knowledge and Innovation Systems (AKIS); thus contributing to the ‘AKIS dimension of National Strategic Plans of the next Common Agricultural Policy, 2023–2027. We argue for the more effective use of advances in the social sciences through a better understanding of advice as social interaction which can bolster the inclusiveness of public policies.

Vacuolar H(+)-ATPase–dependent (V-ATPase–dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell–derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase–dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase–dependent signaling and protein degradation in the developing human central nervous system.

International audience; Understanding the relationship between the organizational characteristics of a farm and its environmental performance is essential to support the agro-ecological transition of farms. This is even more important as very few studies on the subject have been undertaken and as there is a growing diversity of organizational forms of farms that differ from the traditional family model. This paper proposes a comprehensively integrated approach of dairy farms in Brazil. A case study of six archetypes of farms with contrasted organizational characteristics is developed to explore the relations between, on the one hand, farms’ organizational structure and governance, and on the other hand, the adoption of agri-environmental practices. Results show that the adoption of agri-environmental practices varies across the wide range of farm’s organizational forms—from the family to the industrial models. Farms with limited internal resources depend more specifically on external sectoral or territorial resources to implement environmental practices. If the environment is conducive to the creation of incentives and coordination mechanisms underlying learning processes, farms will adopt agri-environmental practices, regardless of they are organized. The creation of local cooperatives, farmer’s networks and universities extension programs can strengthen farmers’ absorption, adaptation and transformation capacities and boost the adoption of environmental practices. Finally, considering farms as heterogeneous organizational forms in terms of human capital, resources, market, and informational access is essential to accelerate the agroecological transition.

Introduction Le marché du foncier agricole français est sous tension et l'accès aux terres agricoles est aujourd'hui particulièrement difficile pour les agriculteurs qui veulent s'agrandir ou s'installer. Selon la Fédération nationale des Safer* (FNSafer) et Terres d'Europe-Scafr 96 , les prix du foncier agricole ont augmenté en moyenne de 40% environ entre 1997 et 2012. Pour autant, ils restent très inférieurs à celui du foncier à bâtir, en particulier en zone périurbaine, ce qui encourage la conversion des terres vers d'autres usages. En l'espace d'un demi-siècle, la France a ainsi vu l'artificialisation de près de 28% de ses terres agricoles. Celles-ci sont par ailleurs de plus en plus convoitées par les investisseurs étrangers car leurs prix, malgré une augmentation continue, restent bien inférieurs à ceux des autres pays européens (FNSafer et Terres d'Europe-Scafr, 2012 ; FNSafer, 2015 ; Levesque, 2016). Il y aurait de moins en moins de terres agricoles à vendre en France. Le volume des transactions des terrains agricoles libres de toute location a été divisé par deux entre 1997 et 2012, au profit du marché de la location. Pour la première fois, en 2010, ce dernier a dépassé celui des ventes. 76% de la surface agricole utile* française sont aujourd'hui cultivés par des agriculteurs qui n'en sont pas propriétaires (Courleux, 2013). Alors que la population agricole ne compte plus qu'un million d'actifs (soit près de 2% de la population active totale), elle ne constitue plus son propre vivier pour assurer sa reproduction. La reprise des exploitations achoppe très souvent sur la question foncière. On assiste à une rétention d'une partie du foncier par d'anciens acteurs de la production agricole au détriment de l'installation de jeunes agriculteurs 97. Le projet patrimonial prime bien souvent sur le projet d'entreprise. Parallèlement, les statistiques publiques nous informent que les exploitations sous forme sociétaire* occupent une place grandissante, et notamment les sociétés civiles ou les sociétés anonymes, jusqu'alors peu communes en agriculture. Entre 1988 et 2010, alors que le nombre d'exploitations individuelles a été divisé par trois, le nombre d'exploitations au statut sociétaire a lui doublé pour atteindre aujourd'hui 30% du total. Le nombre d'acquisitions de terres agricoles réalisées par ces sociétés a triplé entre 1997 et 2012, ce qui a contribué au phénomène de concentration foncière (Levesque et al., 2011 ; FNSafer et Terres d'Europe-Scafr, 2012).

International audience; Burkina Faso is currently facing a serious deterioration of water quality due to the use of pesticides in agriculture, which is an even greater challenge for the government since farmers are unaware of the toxicity of these chemicals. Therefore, reducing pesticide use requires updating farmers' beliefs about the environmental and health consequences of their actions. Drawing on the theory of positional objectivism developed by Sen, this study seeks to determine the influence of various positional characteristics (gender, education level, socio-cultural factors, etc.) on individual beliefs. In so doing, it uses a recursive bivariate probit model. The model was tested using data collected from a sample of 389 farmers. The results from this model showed that the more farmers' had beliefs about the degradation of water quality, the less they were inclined to use pesticides. These beliefs were based on personal lived experiences and were also formed through interactions with other farmers. Moreover, government agencies and NGOs in regular contact with the farmers played a crucial role in shifting the farmers' observational positions.

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International audience; As scholars have shown, acceptance is key to the success of Payment for Ecosystem Services (PES) scheme. While many studies adopt a static cost-benefit perspective, few address the social process leading to acceptance. Drawing on Suchman (1995), this article examines the legitimacy process underlying the acceptance of a PES in agriculture. In particular, the role of collective action in the legitimisation process is analysed, using a combination of qualitative and quantitative methods of discourse analysis. Data from an agro-environmental PES scheme in France on water quality shows that acceptance depends on the normative and cognitive legitimacy that actors confer upon a public policy.

Renin, a key component in the regulation of blood pressure in mammals, is produced by the rare and highly specialized juxtaglomerular cells of the kidney. Chronic stimulation of renin release results in a recruitment of new juxtaglomerular cells by the apparent conversion of adjacent smooth muscle cells along the afferent arterioles. Because juxtaglomerular cells rapidly dedifferentiate when removed from the kidney, their developmental origin and the mechanism that explains their phenotypic plasticity remain unclear. To overcome this limitation, we have performed RNA expression analysis on 4 human renin-producing tumors. The most highly expressed genes that were common between the reninomas were subsequently used for in situ hybridization in kidneys of 5-day-old mice, adult mice, and adult mice treated with captopril. From the top 100 genes, 10 encoding for ligands were selected for further analysis. Medium of human embryonic kidney 293 cells transfected with the mouse cDNA encoding these ligands was applied to (pro)renin-synthesizing As4.1 cells. Among the ligands, only platelet-derived growth factor B reduced the medium and cellular (pro)renin levels, as well as As4.1 renin gene expression. In addition, platelet-derived growth factor B–exposed As4.1 cells displayed a more elongated and aligned shape with no alteration in viability. This was accompanied by a downregulated expression of α-smooth muscle actin and an upregulated expression of interleukin-6, suggesting a phenotypic shift from myoendocrine to inflammatory. Our results add 36 new genes to the list that characterize renin-producing cells and reveal a novel role for platelet-derived growth factor B as a regulator of renin-synthesizing cells.

International audience; En rupture avec l'exploitation familiale traditionnelle, des firmes agricoles se profilent dans de nombreuses régions du globe. Avec elles, s’amorce une recomposition agraire dont les contours restent largement invisibles.À l’exception de quelques cas médiatisés de « mégafermes » et autres « fermes des 1 000 vaches », la majorité de ces firmes ont jusqu’à présent échappé à l’analyse tant leurs visages sont multiples et flous.Leurs performances économiques et financières tout comme leurs incidences environnementales et sociales interrogent aussi bien les milieux politiques, professionnels que scientifiques.Comment sont-elles organisées ? Quels sont leurs logiques et modes d’action ? Dans quels espaces s’inscrivent-elles ? Comment une ferme familiale devient-elle une firme agricole ? Quels types d’acteurs sont impliqués ? Quels rapports au politique entretiennent-elles ? Quels conflits provoquent-elles ?Le premier ouvrage sur un phénomène mondial en pleine émergence.

Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57BI/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.

Since the late 1980s, many alternative practices have been proposed to European farmers to reduce pesticide and input use in general. These practices have been promoted by agro-environmental contracts signed between individual farmers and the European Union and by which farmers engage themselves in changing their practices. The adoption rate of these measures has remained very low in many European regions particularly in Southwestern France. This article aims at stressing the role played by risk attitude and labor constraint in farmers’ adoption decision. After presenting a static theoretical model which assesses the impact of labor constraints and risk attitude on the level of adoption of low input practices supported by agro-environmental contracts, the article proposes a numerical application based on a mathematical programming risk-model implemented on two typical crop farms in South-western France. Three kinds of contracts (no tillage, long rotation, lower pest treatments) are tested, two of them (long rotation and lower pest treatments) aiming at directly reducing input use. The results show that, despite the overall positive impact of alternative practices under contract on environment and farmers’ income, increased yield variability under positive risk aversion and larger labor requirements are actual barriers to adoption., Le rôle de l’aversion au risque et des contraintes de travail dans l’adoption des mesures volontaires agro-environnementales à bas niveau intrants Depuis la fin des années 1980, plusieurs pratiques alternatives ont été soutenues dans le cadre de programmes agro-environnementaux, par des contrats volontaires signés entre l’Union Européenne et les agriculteurs, par lesquels ceux-ci s’engagent à changer durablement leurs pratiques. Le taux d’adoption de ces contrats est resté très faible dans beaucoup de pays de l’UE et dans le sud-ouest de la France en particulier. Cet article vise à analyser le rôle du comportement par rapport au risque et des contraintes de travail sur la décision d’adoption de ces pratiques. Après avoir présenté un modèle théorique statique pour montrer l’impact du risque et du facteur travail dans l’adoption de pratiques à bas niveau d’intrants, nous proposons une application à l’aide d’un modèle de programmation mathématique représentant deux types d’exploitations céréalières spécialisées du sud-ouest de la France. Trois types de contrats agro-environnementaux sont testés (zéro labour, rotation longue, diminution des traitements phytosanitaires). Les résultats montrent que malgré l’effet globalement positif des pratiques alternatives sur les indicateurs environnementaux et sur le revenu des agriculteurs, la variabilité plus forte des rendements, en présence d’aversion au risque positive, ainsi que de plus forts besoins en travail sont des barrières importantes à l’adoption., Ridier Aude, Ben El Ghali Mohamed, Nguyen G., Kephaliacos Charilaos. The role of risk aversion and labor constraints in the adoption of low input practices supported by the CAP green payments in cash crop farms. In: Revue d’études en Agriculture et Environnement, Vol. 94, N°2, 2013. pp. 195-219.

En partant d’une experience multi-partenariale originale de MAET-DCE portee par une cooperative, ce travail se propose d’analyser le role de l’apprentissage collectif sur la reduction des risques lies a l’adoption de pratiques agricoles alternatives. Le processus de transmission de l’information technique ainsi que les formes de coordination associees ont ete analyses en mobilisant des approches principalement de l’economie institutionnelle traitant de l’incertitude et des modalites actuelles du conseil en agriculture. L’analyse montre que l’action de la cooperative est au centre de la creation conjointe de plusieurs categories de biens, reposant sur differents types de transaction informationnelle.

ResumeDans son livre intitule L’espace et le temps en Camargue, Bernard Picon retrace le processus exemplaire de mise en valeur agricole de la Camargue depuis le debut du xixe siecle, territoire predispose a des dynamiques de type industriel en ce que son milieu naturel repute hostile rendait difficile l’installation des communautes paysannes traditionnelles. Aujourd’hui, cette region voit emerger de nouvelles formes d’organisation de la production, que nous tentons de decrire et de caracteriser a partir d’entretiens realises aupres de differents acteurs de la filiere rizicole et d’une photographie des trajectoires recentes des exploitations. Pour presenter cette nouvelle figure que, par defaut, nous nommons « agriculture de firme », nous proposons d’ajouter aux ideaux-types habituels des ideaux-types mieux cibles. Au-dela de cet exercice typologique, nous nous interessons a la coexistence de ces formes societaires avec les formes plus classiques de l’exploitation familiale. Ce travail doit contribuer a une meilleure comprehension des phenomenes en cours, non seulement en Camargue mais aussi dans d’autres regions agricoles francaises.

Adipose tissue dysfunction related to obesity is overwhelmingly associated with increased risk of developing cardiovascular diseases. In the setting of obesity, (pro)renin receptor (PRR) is increased in adipose tissue of mice. We sought to determine the physiological consequences of adipocyte-PRR deficiency using adiponectin-Cre mice. We report a unique model of adipocyte-PRR–deficient mice ( PRR Adi/Y ) with almost no detectable white adipose tissues. As a consequence, the livers of PRR Adi/Y mice were enlarged and demonstrated a marked accumulation of lipids. Adipocyte-specific deficiency of PRR increased systolic blood pressure and the concentration of soluble PRR in plasma. To determine whether adipocyte-PRR was involved in the development of obesity-induced hypertension, mice were fed a low-fat or a high-fat diet for 16 weeks. Adipocyte-PRR–deficient mice were resistant to diet-induced obesity. Both high-fat– and low-fat–fed PRR Adi/Y mice had elevated insulin levels. Interestingly, adipocyte-PRR deficiency improved glucose tolerance in high-fat–fed PRR Adi/Y mice. In response to feeding either low-fat or high-fat diets, systolic blood pressure was greater in PRR Adi/Y mice than in control mice. High-fat feeding elevated soluble PRR concentration in control and PRR Adi/Y mice. In vitro knockdown of PRR by siRNA significantly decreased mRNA abundance of PPARγ (peroxisome proliferator-activated receptor gamma), suggesting an important role for PRR in adipogenesis. Our data indicate that adipocyte-PRR is involved in lipid homeostasis and glucose and insulin homeostasis, and that soluble PRR may be a predictor of metabolic disturbances and play a role in systolic blood pressure regulation.

The prorenin receptor (PRR) is highly expressed in podocytes, but its role in the maintenance of podocyte function is unknown. Here we generated podocyte-specific PRR-knockout mice and found that these animals died between 2 to 3 wk after birth. Within 14 d, PRR-knockout mice developed nephrotic syndrome, albuminuria with podocyte foot-process fusion, and cytoskeletal changes. Podocyte-specific PRR deletion also led to disturbed processing of multivesicular bodies and enrichment of autophagosomal (LC3) and lysosomal (LAMP2) markers, indicating a functional block in autophagosome-lysosome fusion and an overload of the proteasomal protein-degradation machinery. In vitro, PRR knockdown and pharmacologic blockade of vacuolar H(+)-ATPases, which associate with the PRR, increased vesicular pH, led to accumulation of LC3-positive and LAMP2-positive vesicles and altered the cytoskeleton. Taken together, these results suggest that the PRR is essential for podocyte function and survival by maintaining autophagy and protein-turnover machinery. Furthermore, PRR contributes to the control of lysosomal pH, which is important for podocyte survival and cytoskeletal integrity.

The (pro)renin receptor, PRR, was initially characterized as a component of the renin-angiotensin system (RAS). PRR-bound renin and prorenin display increased enzymatic activity, and binding activates intracellular signaling, upregulating the expression of profibrotic proteins. As a consequence, most studies set out to demonstrate a role of PRR in hypertension, cardiovascular and renal diseases, and organ damage, and to identify PRR as a therapeutic target to optimize RAS blockade. The results of animal studies were disappointing and did not convincingly establish PRR as major player in hypertension or in organ damage, although human studies suggested a link between a polymorphism in the PRR gene and blood pressure. New data now suggest that PRR is functionally linked to the vacuolar proton-ATPase and, quite unexpectedly, that PRR is necessary to Wnt signaling pathways that are essential (independently of renin) for adult and embryonic stem cell biology, embryonic development, and diseases including cancer, thereby opening new perspectives on the pathophysiological roles of PRR.

PRR [(pro)renin receptor] was named after its biological characteristics, namely the binding of renin and of its inactive precursor prorenin, that triggers intracellular signalling involving ERK (extracellular-signal-regulated kinase) 1/2. However the gene encoding for PRR is named ATP6ap2 (ATPase 6 accessory protein 2) because PRR was initially found as a truncated form co-purifying with V-ATPase (vacuolar H+-ATPase). There are now data showing that this interaction is not only physical, but also functional in the kidney and the heart. However, the newest and most fascinating development of PRR is its involvement in both the canonical Wnt/β-catenin and non-canonical Wnt/PCP (planar cell polarity) pathways, which are essential for adult and embryonic stem cell biology, embryonic development and disease, including cancer. In the Wnt/β-catenin pathway, it has been shown that PRR acts as an adaptor between the Wnt receptor LRP5/6 (low-density lipoprotein receptor-related protein 5/6) and Fz (frizzled) and that the proton gradient generated by the V-ATPase in endosomes is necessary for LRP5/6 phosphorylation and β-catenin activation. In the Wnt/PCP pathway, PRR binds to Fz and controls its asymetrical subcellular distribution and therefore the polarization of the cells in a plane of a tissue. These essential cellular functions of PRR are independent of renin and open new avenues on the pathophysiological role of PRR. The present review will summarize our knowledge of (pro)renin-dependent functions of PRR and will discuss the newly recognized functions of PRR related to the V-ATPase and to Wnt signalling.

Au Niger, le desengagement de l’Etat de la gestion des grands amenagements hydro-agricoles dans les annees 1980 a conduit a un transfert des responsabilites aux organisations paysannes. L’article analyse les dynamiques de construction de nouvelles regles de gestion locale des amenagements et leur perennite. L’analyse s’articule autour de la notion de "gouvernance hybride", processus enchâsse dans la structure sociale qui garantit l’acces a l’eau mais pas necessairement la viabilite technico-economique des amenagements.

During the 1980s, the diminishing role of the state in numerous sub-Saharan African countries led to the reorganization of relationships among the different actors in the management of irrigation systems. In the new context, many of the tasks were transferred to peasant organizations and user associations. New institutional forms of management and governance of water at the local level have consequently emerged. To analyze the sustainability and efficiency of such local arrangements, the analysis focuses on the articulation between local and global, and in particular, on the joint construction of “hybrid rulesn through “hybrid governance.”

International audience; The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the following: LoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.

Meeting the service needs of the less well-off and the elderly in areas of low density population remains a perennial problem. Increasingly, partnership between two or more of the state, the private and the voluntary sectors is viewed as a strategy for delivering welfare services, as part of new forms of local governance. Previous research points to the influence of established and new institutional and associated territorial structures on the formation and working of partnerships. This paper examines the role of partnerships in home-based welfare service delivery in France and Ireland; countries which share similarities, but also marked differences in their systems of local government and governance. The results reveal that both established and new territorial and institutional structures are influential in moulding approaches to service delivery through partnership. So too is the continuing role of the state, in contrast to some descriptions of the influence of neo-liberalism.

The (pro)renin receptor [(P)RR] specifically binds renin and prorenin and mediates their intracellular effects. It acts as co-factor for renin and prorenin by increasing their enzymatic activity on the cell-surface and it activates the mitogen activated protein kinases ERK1/2 (extracellular signal regulated kinase) cascade leading to cell proliferation and to upregulation of profibrotic genes expression. Studies in genetically modified animals over-expressing ubiquitously (P)RR or specifically in smooth-muscle cells suggest a direct role for (P)RR cardiovascular and renal pathologies. A putative (P)RR blocker consisting in part of the prosegment of prorenin gave spectacular results in the prevention of diabetic nephropathy and cardiac fibrosis but its mechanism of action and its specificity for (P)RR remain controversial. Unexpectedly, the total ablation of (P)RR gene is impossible in contrast to the other components of the renin angiotensin system (RAS) and studies in zebra fish and in embryonic stem cells indicate that (P)RR is necessary to cell survival and proliferation. Furthermore, a mutation of (P)RR is associated with mental retardation and epilepsy, pointing to an essential role of (P)RR in brain development. If the role of (P)RR in cardiovascular and renal diseases can be confirmed in (P)RR knockout animals, the benefit of a (P)RR blocker in order to optimize the tissue RAS blockade should really be addressed but not without a good understanding of all its functions and not only those related to the RAS.

The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the “handle-region” peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of 125 I-renin or 125 I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.

Summary Renin inhibitors are now available in therapeutic doses and it is accepted that they decrease blood pressure as efficiently as the classic inhibitors of the renin-angiotensin system (RAS): angiotensin converting enzyme inhibitors and angiotensin II–receptor blockers (ARBs). One major issue will be to know how, beyond the normalization of blood pressure, renin inhibitors (RIs) will compare with angiotensin converting enzyme inhibitors and ARBs for their ability to protect the organs against the tissue damage associated with overactivation of the RAS. The mechanism(s) of tissue protection may involve the inhibition of a direct cellular effect of renin and prorenin mediated by the (pro)renin receptor ([P]RR). This review updates the recent findings on (P)RR; its role in hypertension, cardiac fibrosis, diabetic nephropathy, and retinopathy; and the effects of a putative (P)RR antagonist.

OBJECTIVE: Mannose 6-phosphate receptors (M6PR) bind both renin and prorenin, and such binding contributes to renin/prorenin clearance but not to angiotensin generation. Here, we evaluated the kinetics of renin/prorenin binding to the recently discovered human (pro)renin receptor (h(P)RR), and the idea that such binding underlies tissue angiotensin generation. METHODS AND RESULTS: Vascular smooth muscle cells from control rats and transgenic rats with smooth muscle h(P)RR overexpression were incubated at 4 or 37 degrees C with human renin or prorenin. Incubation at 37 degrees C greatly increased binding, suggesting that (pro)renin-binding receptors cycle between the intracellular compartment and the cell surface. Blockade of the M6PR reduced binding by approximately 50%. During M6PR blockade, h(P)RR cells bound twice as much prorenin as control cells, while renin binding was unaltered. Incubation of h(P)RR (but not control) cells with prorenin + angiotensinogen yielded more angiotensin than expected on the basis of the activity of soluble prorenin, whereas angiotensin generation during incubation of both cell types with renin + angiotensinogen was entirely due to soluble renin. The renin + angiotensinogen-induced vasoconstriction of isolated iliac arteries from control and transgenic rats was also due to soluble renin only. The recently proposed (P)RR antagonist 'handle region peptide', which resembles part of the prosegment, blocked neither prorenin binding nor angiotensin generation. CONCLUSIONS: H(P)RRs preferentially bind prorenin, and such binding results in angiotensin generation, most likely because binding results in prorenin activation.

Although Wnt/β-catenin signaling is known to be aberrantly activated in PDAC, mutations of CTNNB1, APC or other pathway components are rare in this tumor type, suggesting alternative mechanisms for Wnt/β-catenin activation. Recent studies have implicated the (pro)renin receptor ((P)RR) is related to the Wnt/β-catenin signaling pathway. We therefore investigated the possible role of (P)RR in pancreatic carcinogenesis. Plasma s(P)RR levels were significantly (P < 0.0001) higher in patients with PDAC than in healthy matched controls. We also identified aberrant expression of (P)RR in premalignant PanIN and PDAC lesions and all the PDAC cell lines examined. Inhibiting (P)RR with an siRNA attenuated activation of Wnt/β-catenin signaling pathway and reduced the proliferative ability of PDAC cells in vitro and the growth of engrafted tumors in vivo. Loss of (P)RR induced apoptosis of human PDAC cells. This is the first demonstration that (P)RR may be profoundly involved in ductal tumorigenesis in the pancreas.

National audience

Sustainable agriculture and ways to achieve it are important issues for agricultural policy. However, the concept of sustainability has yet to be made operational in many agricultural situations, and only a few studies so far have addressed the implementation process of sustainable agriculture. This paper provides an assessment of the Territorial Farming Contracts (TFC) – the French model for implementing sustainable agriculture – and aims to give some insights into the ways to facilitate the development of sustainable farming. Using a systems approach, the founding concept of the TFC model, an analysis has been made of the TFCs signed in the Midi-Pyrenees Region in south-western France. The results show that the first aspect of sustainability apparent in farmers’ projects referred to economic objectives. The environmental and social aspects were not foremost in the farming changes undertaken. In addition, the territorial dimension of the TFC was under-addressed. The majority of TFCs reveal a moderate or even low convergence with territorial priorities. These results are explained partly by the dominance of professional farming organizations in the implementation of TFC, and they imply that the organizational social dimensions of sustainability must not be neglected.

There is a widespread consensus about the importance of sustainable agriculture. In France, the Farming Orientation Law of July 1999 has set down a precise procedure for the implementation of sustainable agriculture: the contrat territorial d’exploitation – or territorial farm contract (TFC). This paper aims to analyse the TFC effectiveness. An analysis has been made of the TFCs signed in the Midi-Pyrenees Region in south-western France, using statistical analysis and qualitative surveys of a sample of farms. The results show that the most valuable effects have been mainly economic. Effects regarding social and environmental aspects were very limited. But from the point of view of an integrated approach, indirect effects of TFCs can be observed on social and environmental aspects. These results are explained, on the one hand, by farmers’ motivations guided by economic objectives, and on the other hand, by the dominance of professional farming organisations in the implementation of TFC’s procedure. Given these results, two ways of improving the elaboration procedure for TFCs are proposed. Firstly, technical improvements can be made to the diagnostic assessment of farms, and to the choice of actions addressed by the contract. Secondly, organisational improvements can be applied to TFCs elaboration and implementation process, in order to adopt a participatory approach which would involve all rural stakeholders.

The existence of a tissue renin-angiotensin (RAS) system independent of the circulating RAS has prompted the search for cellular binding sites for angiotensinogen and for renin in order to explain their tissue uptake. Two receptors that bind with similar affinity mature renin and prorenin were identified, the mannose-6-phosphate receptor (M6P-R) and a specific receptor. The M6P-R is a clearance receptor that binds exclusively the glycosylated forms of renin and prorenin. Binding of renin and prorenin to the M6P-R is followed by internalization and degradation, and the intracellular proteolysis of prorenin in mature renin did not provoke any generation of intracellular angiotensins. In contrast to the M6P-R, (pro)renin bound to the specific receptor was not degraded. Instead, receptor-bound renin showed increased catalytic activity, and receptor-bound prorenin exhibited full catalytic activity. This 'gain of activity' was explained by a conformational change of the (pro)renin molecule upon binding. Furthermore, (pro)renin binding provoked a rapid activation of the mitogen-activated protein kinases p44/p42, indicating that the receptor has mediated specific, angiotensin II-independent effects of (pro)renin. This receptor represents an elegant concept to explain the existence of active prorenin in vivo, and it provides a pathological role for prorenin in situations with paradoxical low renin and high prorenin concentrations such as in diabetes. Experimental models of rats overexpressing the receptor either in vascular smooth muscle cells and developing high blood pressure or with ubiquitous expression associated with glomerulosclerosis and proteinuria confirm a role for the receptor in cardiovascular and renal diseases.

Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.8±5 versus 118.9±3.7 mm Hg; P =0.008), and an augmentation in heart rate (349.1±7.7 versus 303.1±16.16 bpm; P =0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 428±64.9 versus 207.3±73.24 pg/mL in control; P =0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.04±2.2 versus 2.8±0.55 in control; P =0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR).

L’article s’interesse a un dispositif institutionnel particulier appele les mesures agro-environnementales territorialisees Directive cadre sur l’eau (MAET-DCE). Ce dispositif a ete introduit par les pouvoirs publics en 2007 pour inciter les agriculteurs a recourir a des pratiques davantage respectueuses de la ressource en eau. Toutefois, l’adhesion des agriculteurs a un changement de pratiques est loin d’etre acquise. Partant de ce constat, l’article vise a montrer que le dispositif MAET en tant qu’innovation institutionnelle et technique ne pourra produire les effets escomptes, a savoir contribuer a ameliorer la qualite de l’eau, que s’il devient acceptable aux yeux des agriculteurs impliques. Le concept de legitimite sert a preciser les conditions requises a cette acceptation. L’experience relativement reussie d’une MAET-DCE conduite en Midi-Pyrenees est utilisee comme cas d’etude. D’un point de vue conceptuel, les contributions d’auteurs en economie, comme Amartya Sen, Daniel Bromley et Arild Vatn servent a mieux comprendre comment des acteurs peuvent collectivement actualiser leurs croyances et leurs raisons d’agir, et par ce biais legitimer le changement de pratiques agricoles vehicule par une mesure de politique publique. En coherence avec le cadre d’analyse theorique, la demarche methodologique combine une analyse du compromis institutionnel sur lequel repose le dispositif MAET-DCE et une analyse comparative des croyances sous-jacentes aux raisons d’agir des agriculteurs engages et non engages dans la MAET etudiee. Ces croyances sont constatees au travers des pratiques agricoles effectives et a travers les discours d’acteurs, agriculteurs et conseillers MAET.

Our model of the renin-angiotensin system has become increasingly complex with the identification of new components and additional roles for angiotensin peptides and their receptors. A functional (pro)renin receptor has been cloned. It acts as (pro)renin co-factor on the cell surface, enhancing the efficiency of angiotensinogen cleavage by (pro)renin and unmasking prorenin catalytic activity. Binding of (pro)renin to the receptor mediates (pro)renin cellular effects by activating MAP kinases ERK1/2. Immunofluorescence studies have located the receptor on mesangial and vascular smooth-muscle cells in human heart and kidney. This suggests that the renin receptor may represent a mean of capturing (pro)renin from the circulation and concentrating it at the interface between smooth-muscle and endothelial cells. This recent discovery of a functional (pro)renin receptor forces the emergence of a new concept that casts renin as potentially playing a direct role in tissue damage, especially in situations where the tissue RAS is activated.

With respect to the idea of multifunctional agriculture, one way to raise farmers' environmental stewardship is to reward environmental practices through food quality labelling schemes. The objective of our study was to identify existing relationships between the production of quality food and the production of environmental goods at farm level. In this article, we report the results of analyses conducted to examine the effects of major ‘quality’ and ‘eco-labelling’ schemes in the Midi-Pyrenees region of the south of France. Factor analysis and analysis of variance were used with a data set of 107 farms—some participating in the labelling schemes and some not participating—for which environmental scores had been assigned. The statistical analyses were complemented by a qualitative analysis based on in-depth interviews of 85 farmers and review of the labelling standard guidelines. This study shows that organic farms and farms enrolled in various quality and eco-labelling programmes in France do provide som...

Le role des proteases et des antiproteases dans la progression de l’insuffisance renale chronique a ete bien documente. La plupart des etudes ont concerne la plasmine et les activateurs du plasminogene de la famille des serine-proteases, et les metalloproteases matricielles. Recemment, l’attention s’est portee sur la renine, une aspartyl-protease. La renine est une enzyme essentielle du systeme renine angiotensine et le clivage de l’angiotensinogene en angiotensine I est l’etape limitante de la generation d’angiotensine II (Ang II), puissant peptide vaso-actif egalement implique dans les processus de fibrose renale. Notre groupe vient de cloner un recepteur fonctionnel de la renine. La fixation de la (pro)renine est associee a deux evenements majeurs : d’une part, l’augmentation de l’activite catalytique de la (pro)renine pour son substrat l’angiotensinogene, d’autre part, l’activation des MAP kinases ERK1/2 (Extracellular Regulated Kinases) dont on connait le role dans les processus de differenciation, d’hypertrophie et de proliferation cellulaires. L’analyse immunohistochimique de coupes de cœur et de rein humains normaux montre que le recepteur de la renine est trouve dans les arteres coronaires et renales, ainsi que dans les glomerules, associe aux cellules musculaires lisses vasculaires et aux cellules mesangiales glomerulaires. Dans les cellules musculaires lisses, la conversion de l’angiotensine I en Ang II serait plus efficace du fait de la proximite de l’enzyme de conversion membranaire et les effets biologiques seraient optimises, l’Ang II etant generee au voisinage des ses recepteurs. L’analyse par Northern blot indique que l’ARN messager du recepteur est tres abondamment exprime dans le cœur, le cerveau et le placenta, et a un moindre degre dans le rein, le foie et le pancreas.

Matrix metalloproteinase 2 (MMP2) has been reported to be secreted by collagen-stimulated platelets, and active MMP2 has been shown to play a role in platelet aggregation. It has been demonstrated that MMP2 activation is dependent on the complex (membrane type 1 [MT1]-MMP/tissue inhibitor of MMP2 [TIMP2]) receptor and MMP2. We have investigated human platelets as a possible source of MT1-MMP, and we have studied its role in MMP2 activation and in platelet aggregation. Gelatin zymograms showed the existence of MMP2 at proforms (68 kd) and activated-enzyme forms (62-59 kd) in supernatants of resting and activated platelets, respectively. No gelatinolytic activity was associated with the platelet pellet after aggregation, suggesting a total release of MMP2 during cell activation. By Western blot analysis in nonreduced conditions, MT1-MMP was found on resting platelet membranes in 2 forms–the inactive 45-kd form and an apparent 89-kd form, which totally disappeared under reduced conditions. After platelet degranulation, only the 45-kd form was detected. Reverse transcription–polymerase chain reaction experiments showed the expression in platelets of messenger RNA encoding for MMP2, MT1-MMP, and TIMP2. Flow cytometry analysis showed that MT1-MMP, MMP2, and TIMP2 expressions were enhanced at the activated platelet surface. MMP inhibitors, recombinant TIMP2, and synthetic BB94 inhibited collagen-induced platelet aggregation in a concentration-dependent manner, indicating the role of activated MT1-MMP in the modulation of platelet function. In conclusion, our results demonstrate the expression of the trimolecular complex components (MT1-MMP/TIMP2/MMP2) by blood platelets as well as the ability of MMP inhibitors to modulate the aggregating response.

PAI-1 secretion and matrix deposition in human peritoneal mesothelial cell cultures: Transcriptional regulation by TGF- β 1. Background Plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of plasminogen activators in plasma and in peritoneum, impairs plasmin formation that is essential for the repair processes of the mesothelium damaged by peritoneal dialysis fluids and peritonitis. The fibrogenetic cytokine transforming growth factor- β (TGF- β ) displays variable effects on extracellular matrix remodeling enzymes and their inhibitors depending on tissues and cell lines. We previously found an unexpected stimulating effect of TGF- β 1 on matrix metalloproteinase-9 in peritoneal mesothelial cells. In this study, we analyzed the effects of TGF- β 1 on PAI-1 production and deposition in extracellular matrix. Methods We used primary cultured mesothelial cells and a recently established human peritoneal mesothelial cell line (HMrSV5). Cell-associated and secreted plasminogen activators and their inhibitors were detected and characterized by substrate gel zymography. PAI-1 was identified by reverse zymography and by Western blotting, and total PAI-1 was measured by ELISA. Secreted and cell-associated PA activity was measured by its ability to activate plasminogen into plasmin, that is, by the release of paranitroaniline from the plasmin synthetic substrate S-2251. PAI-1 mRNA accumulation was assessed by Northern blot. In vitro nuclear run-on assays were carried out to determine whether TGF- β 1 had transcriptional effects on PAI-1 expression. Finally, the subcellular distribution of PAI-1 was analyzed by immunofluorescence and by immunogold silver staining. Results TGF- β 1 increased PAI-1 antigen in the conditioned media of HMrSV5 cells, in a time- and concentration-dependent manner. This induced a dramatic decrease of free tPA in the cell medium and of membrane-bound uPA, and a parallel increase of high molecular weight PA-PAI complexes. Consequently, secreted and cell-associated plasminogen activator activities were considerably reduced. In primary cultured peritoneal mesothelial cells, TGF- β 1 also induced PAI-1 secretion and the shift of tPA toward high molecular weight complexes. TGF- β 1 increased PAI-1 mRNA in a time- and concentration-dependent manner. This effect was at least in part transcriptional since an ∼threefold increase in the rate of PAI-1 gene transcription was observed in nuclei sampled after a four-hour cell exposure to 5ng/ml TGF- β 1. Finally, TGF- β 1 substantially increased the amount of intracellular and matrix-associated PAI-1. Conclusions These results suggest that excessive TGF- β 1-stimulated PAI-1 could prevent appropriate peritoneal healing by impairing the degradation of fibrin and of unorganized matrix components, and by interfering with cell migration.

Interaction between the renin-angiotensin system and cyclooxygenases in the kidney regulates renal microcirculation. Activation of the (pro)renin receptor has profibrotic effects, and now Kaneshiroet al. show that it also increases COX-2 synthesis. These results may have therapeutic implications, as blocking (pro)renin-receptor interaction would prevent the increase of angiotensin generation and prostaglandin synthesis, two phenomena underlying the pathogenesis of diabetic nephropathy.

In agricultural landscapes farmers have a large impact on biodiversity through the management decisions they apply to their land. Farmers' perceptions of biodiversity and its different values influence their willingness to apply biodiversity friendly farming practices. The results of a discourse-based, deliberative biodiversity valuation are presented in this paper. Organic and conventional farmers' perceptions of the different values of biodiversity were analyzed across three European countries. Focus group methodology was used to explore how farmers perceive biodiversity and how they assess its values. Our results suggest that farmers' perceptions of biodiversity are strongly embedded in their everyday lives and linked to farming practices. Besides recognizing the importance of species and habitat diversity, farmers also acknowledge wider landscape processes and attach value to the complexity of ecological systems. Organic farmers tended to have a more complex and philosophical approach to biodiversity and they were relatively homogeneous in this aspect, while conventional farmers showed larger heterogeneity. Ethical and social values were important for all farmers. Economic value was more dominant in the conventional focus groups. The discourse based deliberative valuation method is worth applying in relation to biodiversity for two reasons. First, this method is able to reflect the heterogeneity of non-scientist participants and the context in which they are embedded, which both have a great impact on the results of the valuation. Second, deliberation upon the importance of biodiversity makes possible to understand the competing perceptions of biodiversity and to include different value aspects in the valuation process. The policy oriented consequence of the research can be drawn from the observation that farmers have a strong acknowledgement of ethical and social biodiversity values. This suggests that soft policy tools could also foster biodiversity sensitive farming methods, complementary to mainstream monetary incentives.

Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Some proteases possess a membrane receptor that focalizes their proteolytic activity on the cell surface and may mediate a proliferative effect, such as urokinase on glomerular epithelial cells. Since some hypertensive states are associated with high concentrations of renin and proliferation of arteriolar smooth muscle cells, we asked whether renin, an aspartyl-protease, would bind to mesangial cells that are smooth-muscle derived cells, which would induce their proliferation. The binding of 125 I labeled recombinant human renin ( 125 I-R) was studied on human primary mesangial cells and mesangial cells immortalized by transfection with SV40-T antigen. At 37°C, the binding of 125 I-R was time dependent and reached a plateau after two hours. 125 I-R was found to bind in a saturable and specific manner with a K d = 0.4nM and 1nM and 8,000 and 2,000 binding sites/cell, for primary and immortalized cells, respectively. When binding experiments were performed in the presence RO 42-5892, a synthetic inhibitor of renin, RO 42-5892 could inhibit the specific binding of labeled renin only at concentrations 1,000 times superior to the IC 50, indicating that the renin-mesangial receptor interaction did not depend on the active site of renin. Analysis by SDS-PAGE and autoradiography of cross-linking experiments of 125 I-R bound to a membrane preparation showed a band of approximately 110 to 120 kDa, suggesting a Mr of 70 to 80kDa for the renin receptor. Incubation of mesangial cells with 100nM renin for 24 hours provoked a 100% increase of 3 H thymidine incorporation that was not accompanied by an increase of the cell number, even after a seven day period of incubation. However, the incubation of mesangial cells with renin for 24 hours induced a significant increase (170% of control, P = 0.04) of plasminogen activator inhibitor-1 (PAI1) antigen in the conditioned medium. In conclusion, we have shown that human mesangial cells in culture express a specific receptor for renin, and that the binding of renin increases 3 H thymidine incorporation independently of renin enzymatic activity. The absence of cell proliferation, the increase of 3 H thymidine incorporation and the increase of PAI1 antigen suggest that the binding of renin can induce mesangial cell activation, which is reflected by a change in the fibrinolytic capacity of the cells. The role of this receptor remains to be determined in nephropathies and hypertensive states associated with high plasma/tissue renin concentrations, hypertrophy of mesangial or smooth muscle cells and extracellular matrix remodeling.