title: Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis.
abstract: Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling.
authors.affiliation: Departamento de Medicina, Laboratório de Imunologia Clínica e Experimental, Disciplina de Nefrologia, Universidade Federal de São Paulo, Brazil.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Pereira
authors.forename: Bruna N
authors.initials: BN
authors.lastname: Buscariollo
authors.forename: Matheus
authors.initials: M
authors.lastname: Corrêa-Costa
authors.forename: Patricia
authors.initials: P
authors.lastname: Semedo
authors.forename: Cassiano D
authors.initials: CD
authors.lastname: Oliveira
authors.forename: Vanessa O
authors.initials: VO
authors.lastname: Reis
authors.forename: Edgar
authors.initials: E
authors.lastname: Maquigussa
authors.forename: Ronaldo C
authors.initials: RC
authors.lastname: Araújo
authors.forename: Tárcio T
authors.initials: TT
authors.lastname: Braga
authors.forename: Maria F
authors.initials: MF
authors.lastname: Soares
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.forename: Denise M A C
authors.initials: DM
authors.lastname: Malheiros
authors.forename: Alvaro Pacheco-Silva
authors.initials: AP
authors.lastname: Filho
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Keller
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Câmara
mesh_terms: D000185:Actinin / Q000378:metabolism; D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D065169:Bradykinin B1 Receptor Antagonists; D004195:Disease Models, Animal; D004317:Doxorubicin; D005786:Gene Expression Regulation / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051547:Heme Oxygenase-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: C491752:Actn4 protein, mouse; D065169:Bradykinin B1 Receptor Antagonists; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D019715:Tissue Inhibitor of Metalloproteinase-1; C113267:nephrin; D000185:Actinin; C024626:bradykinin, des-Arg(9)-; C051090:bradykinin, Leu(8)-des-Arg(9)-; D004317:Doxorubicin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D001920:Bradykinin