title: Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor.
abstract: Mesangial matrix expansion is an early lesion leading to glomeruloclerosis and chronic renal diseases. A beneficial effect is achieved with angiotensin I-converting enzyme inhibitors (ACEI), which also favor bradykinin (BK) B2 receptor (B2R) activation. To define the underlying mechanism, we hypothesized that B2R activation could be a negative regulator of collagen synthesis in mesangial cells (MC). We investigated the effect of BK on collagen synthesis and signaling in MC. Inflammation was evaluated by intercellular adhesion molecule-1 (ICAM-1) expression. BK inhibited collagen I and IV synthesis stimulated by high glucose, epithelial growth factor (EGF), and transforming growth factor-β (TGF-β) but did not alter ICAM-1. Inhibition of collagen synthesis was B2R but not B1R mediated. PKC or phosphatidylinositol 3-kinase (PI3K) inhibitors mimicked the BK effect. B2R activation inhibited TGF-β- and EGF-induced Erk1/2, Smad2/3, Akt S473, and EGFR phosphorylation. A phosphatase inhibitor prevented BK effects. The in vivo impact of B2R on mesangial matrix expansion was assessed in streptozotocin-diabetic rodents. Deletion of B2R increased mesangial matrix expansion and albuminuria in diabetic mice. In diabetic rats, matrix expansion and albuminuria were prevented by ACEI but not by ACEI and B2R antagonist cotreatment. Consistently, the lowered BK content of diabetic glomeruli was restored by ACEI. In conclusion, deficient B2R activation aggravated mesangial matrix expansion in diabetic rodents whereas B2R activation reduced MC collagen synthesis by a mechanism targeting Erk1/2 and Akt, common pathways activated by EGF and TGF-β. Taken together, the data support the hypothesis of an antifibrosing effect of B2R activation.
authors.affiliation: INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier, Toulouse Cedex. France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Blaes
authors.forename: Christiane
authors.initials: C
authors.lastname: Pécher
authors.forename: Marion
authors.initials: M
authors.lastname: Mehrenberger
authors.forename: Eric
authors.initials: E
authors.lastname: Cellier
authors.forename: Françoise
authors.initials: F
authors.lastname: Praddaude
authors.forename: Jacques
authors.initials: J
authors.lastname: Chevalier
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.forename: Réjean
authors.initials: R
authors.lastname: Couture
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Girolami
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024141:Collagen Type IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013311:Streptozocin / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D043782:Receptor, Bradykinin B2; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D001920:Bradykinin