title: ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats.
abstract: Diabetic nephropathy (DN) is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-beta1 (TGF-beta-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-beta-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U858 eq 5, Louis Bugnard Institute, Toulouse Cedex 4, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Allard
authors.forename: Marie
authors.initials: M
authors.lastname: Buléon
authors.forename: Eric
authors.initials: E
authors.lastname: Cellier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Renaud
authors.forename: Christiane
authors.initials: C
authors.lastname: Pecher
authors.forename: Françoise
authors.initials: F
authors.lastname: Praddaude
authors.forename: Marc
authors.initials: M
authors.lastname: Conti
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Girolami
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000187:drug effects / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D020840:Tissue Kallikreins / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D013311:Streptozocin; C065679:icatibant; D017526:Receptor, IGF Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D007703:Peptidyl-Dipeptidase A; D020840:Tissue Kallikreins; D001920:Bradykinin