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ABSTRACT: The renin-angiotensin system (RAS) has become increasingly complex. New components have been identified, and additional roles for angiotensin peptides and their receptors are being uncovered. A functional (pro)renin receptor has been cloned that acts as (pro)renin cofactor on 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 mitogen-activating protein (MAP) kinases, extracellular signal-regulated kinases (ERK)1/2. Immunofluorescence studies have localized the receptor on mesangial and vascular smooth muscle cells in human heart and kidney. This suggests that the renin receptor might represent a means to capture (pro)renin from the circulation and to concentrate (pro)renin at the interface between smooth muscle and endothelial cells. In this article, we review the biochemical characteristics of this receptor and of other renin-binding proteins, and discuss their physiologic significance.
Current Hypertension Reports 05/2004; 6(2):129-32. · 2.50 Impact Factor
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Nephrology Dialysis Transplantation 05/2004; 19(4):981-3. · 3.40 Impact Factor
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ABSTRACT: In membranous nephropathy, the development of glomerular lesions is related to the formation of immune complexes at subepithelial sites. These deposits are associated with modifications in the fibrinolytic activity of glomerular cells leading to the appearance of fibrin degradation products in the deposits and the urine. A previous study has shown that immune complexes interact with glomerular epithelial cells (GEC) through the neonatal Fc receptor (FcRn). We therefore determined whether this binding could be responsible for a modification in the fibrinolytic activity of GEC.
Endocytosis of heat-aggregated immunoglobulins (AgIgG) in cultured human GEC was studied by immunofluorescence and confocal microscopy. The release of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI) by GEC or whole glomeruli was assessed by ELISA, fibrin zymography and Northern blot.
Human GEC in culture bound AgIgG that possess characteristics similar to soluble immune complexes and internalized them by 10 min. This process was mediated by FcRn since chicken aggregated IgG (AgIgY), that do not bind FcRn, did not colocalize with AgIgG in GEC. AgIgG but not AgIgY induced a decrease of FcRn expression at the membrane and within the cells. The binding of AgIgG to GEC elicited a dose- and time-dependent increase in the release of uPA activity, as in the uPA protein and mRNA expression without modification in the release of PAI. This process was not abrogated by agents inhibiting endocytosis and/or transcytosis such as cytochalasin B, suggesting an endocytosis-independent uPA regulation.
GEC response to AgIgG overload comprises at least two sequential steps: (1) a FcRn-mediated endocytosis; (2) an endocytosis-independent fibrinolytic imbalance leading to plasmin generation which could favor in vivo AgIgG clearance and matrix remodeling.
Nephron Experimental Nephrology 02/2004; 98(1):e13-21. · 1.86 Impact Factor
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ABSTRACT: The renin-angiotensin system plays a major role in the control of blood pressure and of salt balance, but it is also involved in physiological and pathological processes, development, inflammation and cardiac hypertrophy. A concept has emerged suggesting that these effects are due to a local activation of the renin-angiotensin system. The search for a receptor of renin was based on the idea that tissue (pro)renin is taken up from the circulation and on data suggesting that renin has cellular effects independent of angiotensin II.
Endothelial cells and cardiac myocytes bind (pro)renin via the mannose-6-phosphate receptor, mainly a clearance receptor as no cellular effect has been specifically attributed to prorenin binding. A functional receptor was cloned recently. It mediates intracellular signalling by activating the mitogen activated protein kinases, extracellular signal regulated kinases 1 and 2, and acts as a co-factor by increasing the efficiency of angiotensinogen cleavage by receptor-bound (pro)renin. The receptor is abundantly expressed in heart, brain, placenta and eye, compared with a lower expression in liver and kidney. In normal human kidney and heart, it is localized in the mesangium and in the coronary and kidney artery, associated with smooth-muscle cells and co-localized with renin.
This receptor provides a functional role for prorenin and may help to understand the physiological and pathological role of elevated levels of prorenin and of local activation of the renin-angiotensin system. From a practical point of view, it questions the need for a pharmacological compound blocking (pro)renin binding and activity as an alternative to the classical inhibitors of the renin-angiotensin system.
Current Opinion in Nephrology and Hypertension 02/2003; 12(1):51-5. · 4.33 Impact Factor
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ABSTRACT: Haemolytic uraemic syndrome (HUS) is a rare and severe disease of various aetiologies in adults. The effect of fresh frozen plasma (FFP) infusion in adults suffering from HUS is not well defined. The aim of this retrospective study was to analyse the causes of HUS in adults admitted in a single renal intensive care unit (ICU) and to determine the life and renal prognosis factors, while most patients (78%) received FFP infusion.
We recorded clinical, biological, and histological data of 55 adults admitted in our renal ICU for HUS between 1990 and 1998, 49 of them having had a renal biopsy. By stepwise logistic regression analysis, we examined the parameters that were associated with the in-hospital mortality and renal function at discharge.
HUS complicated different diseases in 40 patients (HIV infection n=18, nephropathies n=10, allotransplantation n=7, malignant diseases n=5) and appeared as a primary in 15 patients. Factors influencing the in-hospital mortality were positive HIV serology (odds ratio (OR) >20, P=0.0002) and requirement for haemodialysis (OR >35, P=0.004). A pre-existing nephropathy was a bad prognosis factor for renal function (OR >99, P=0.02), while fever was associated with better renal prognosis (OR=1/10, P=0.033).
HUS in adults remains a severe disease, with a high mortality rate in HIV patients and in those who required haemodialysis. However, as compared with previous studies, we observed an improvement in renal outcome, particularly in patients with primary HUS, suggesting a beneficial effect of FFP infusion, at least in these forms.
Nephrology Dialysis Transplantation 07/2002; 17(7):1228-34. · 3.40 Impact Factor
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ABSTRACT: Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors. We report the expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2. High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver. By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin. The renin receptor is the first described for an aspartyl protease. This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.
Journal of Clinical Investigation 07/2002; 109(11):1417-27. · 15.39 Impact Factor
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Nephrology Dialysis Transplantation 04/2002; 17(3):492-4. · 3.40 Impact Factor
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Jean-Daniel Sraer
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ABSTRACT: In France, 45,000 patients are treated by hemodialysis and/or transplantation for chronic renal failure. Every year 7,000 new patients need such a therapeutic approach. The estimated cost of this pathology is about 1% of the total amount of the budget of social security, even though the number of patients is limited. Some treatments were shown to be effective in improving the progression of chronic renal failure, as for example the anti-hypertensive therapy and the adequate treatment of diabetes mellitus. Collagen deposition in each segment of the kidney, mainly in the interstitium, plays a pivotal role in the progression of renal deficiency in chronic renal failure. In order to ameliorate the progression renal failure it would be essential to know: 1) the different types of collagen deposit; 2) the proteinase/antiproteinase systems involved in the remodelling of the extracellular matrix (serine-protease, metallo-protease and their inhibitors); 3) the autocrine/paracrine effects of proteases and of growth factors on collagen synthesis. The more precise the knowledge of these factors, the more useful will be new pharmacological-, gene- or cellular therapies for limiting the progression of chronic renal failure.
Journal de la Société de Biologie 02/2002; 196(4):267-8.
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ABSTRACT: The role of proteases and of antiproteases in the progression of renal disease is well established. Most studies have focused on the serine-proteases of the plasmin/plasminogen activator system and on matrix metalloproteases. Recently, renin, an aspartyl-protease, has attracted much attention because of the role of angiotensin II in the progression of renal lesions and because of the discovery of a functional renin receptor. This receptor is a 45 kDa membrane-protein that binds specifically renin and prorenin. The binding of renin induces an increase of the catalytic efficiency of angiotensinogen conversion into angiotensin I by receptor-bound renin compared to renin in soluble phase, and a rapid phosphorylation of the receptor on serine and tyrosine residues associated with an activation of MAP kinases ERK1/2. Immunofluorescence and confocal analyses on normal human kidney and cardiac biopsies show that the receptor is localized within the mesangial area of glomeruli and in the sub-endothelium of kidney and coronary arteries, associated to smooth-muscle cells. In summary, this receptor exerts dual effects, mediating renin cellular response and increasing the efficiency of angiotensinogen cleavage by membrane-bound renin. These observations emphasizes the importance of angiotensin II generation at the cell surface and the cellular effects of renin add new dimensions (and complexity) to the classical dogma that angiotensin II is the only effector of the RAS.
Journal de la Société de Biologie 02/2002; 196(4):281-4.
