title: Cellular localisation of the kinin B1R in the pancreas of streptozotocin-treated rat and the anti-diabetic effect of the antagonist SSR240612.
abstract: The mechanism by which kinin B1 receptor (B1R) contributes to type 1 diabetes is addressed by determining the impact of its inhibition on diabetes and on its pancreatic expression and cellular localisation on immunocompetent cells and primary sensory C-fibres. Rats were made diabetic with streptozotocin (STZ). On day 4, they were treated daily for 7 days with a B1R antagonist (SSR240612, 10 mg/kg) or its vehicle. The surviving β-cells were measured by immunostaining. The expression of B1R, iNOS, TNF-α, macrophages, TCD4+, CGRP and TRPV1 was measured by Western blotting, qRT-PCR and immunofluorescence. Macrophages and TCD4+ lymphocytes were absent in control, but distributed abundantly in the pancreas of STZ-diabetic rats. B1R was upregulated on these immune cells infiltrating the diabetic rat pancreas while it was not expressed on primary sensory C-fibres even if the expression of TRPV1 and CGRP was enhanced. SSR240612 prevented the infiltration of macrophages and TCD4+ lymphocytes and the upregulation of B1R, iNOS, TNF-α and TRPV1. SSR240612 corrected hyperglycaemia and hypoinsulinaemia by improving the Langerhans islets survival or regeneration. It is concluded that kinin B1R antagonism exerts anti-diabetic action by preventing the infiltration of immune cells in the pancreas and by preserving the integrity of Langerhans islets β-cells.
authors: Nejla
authors: N
authors: Tidjane
authors: Louis
authors: L
authors: Gaboury
authors: Réjean
authors: R
authors: Couture
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D013311:Streptozocin; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D004149:Dioxoles; D007004:Hypoglycemic Agents; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D013311:Streptozocin