Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy.
Renal fibrosis is the common histological feature of advanced glomerular and tubulointerstitial disease leading to end-stage renal disease (ESRD). However, specific antifibrotic therapies to slow down the evolution to ESRD are still absent. Because persistent inflammation is a key event in the development of fibrosis, we hypothesized that the proinflammatory kinin B1 receptor (B1R) could be such a new target. Here we show that, in the unilateral ureteral obstruction model of renal fibrosis, the B1R is overexpressed and that delayed treatment with an orally active nonpeptide B1R antagonist blocks macrophage infiltration, leading to a reversal of the level of renal fibrosis. In vivo bone marrow transplantation studies as well as in vitro studies on renal cells show that part of this antifibrotic mechanism of B1R blockade involves a direct effect on resident renal cells by inhibiting chemokine CCL2 and CCL7 expression. These findings suggest that blocking the B1R is a promising antifibrotic therapy.
Klein
J
J
INSERM, Department of Renal and Cardiac Remodeling-Team 5, 1 av Jean-Poulhes, 31432 Toulouse, France.
Gonzalez
J
J
Duchene
J
J
Esposito
L
L
Pradère
J P
JP
Neau
E
E
Delage
C
C
Calise
D
D
Ahluwalia
A
A
Carayon
P
P
Pesquero
J B
JB
Bader
M
M
Schanstra
J P
JP
Bascands
J L
JL
D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D018932:Chemokine CCL2 / Q000378:metabolism; D054410:Chemokine CCL7 / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004149:Dioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005355:Fibrosis / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
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; D065169:Bradykinin B1 Receptor Antagonists; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D004149:Dioxoles; D012333:RNA, Messenger; D013449:Sulfonamides; D055513:Connective Tissue Growth Factor