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Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy

J. Klein^*,,1, J. Gonzalez^*,,1, J. Duchene^*,, L. Esposito, J. P. Pradère^*,, E. Neau^*,, C. Delage^*,, D. Calise^||, A. Ahluwalia, P. Carayon^¶, J. B. Pesquero^#, M. Bader^**, J. P. Schanstra^*,,2 and J. L. Bascands^*,,2

^* INSERM, Department of Renal and Cardiac Remodeling–Team 5, Toulouse, France;

Université Toulouse III Paul Sabatier, Toulouse, France;

William Harvey Research Institute, Barts, and the London Medical School, London, UK;

Nephrology and Kidney Transplantation Department, CHU Rangueil, Toulouse University Hospital, Toulouse, France;

^|| INSERM, Zootechny Department of Experimental Micro-Surgery, Toulouse, France;

^¶ Sanofi-Aventis R&D, Montpellier, France;

^# Department of Biophysics, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil; and

^** Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

² Correspondence: INSERM, Department of Renal and Cardiac Remodeling–Team 5, 1 av Jean-Poulhes, 31432 Toulouse, France. E-mail: J.L.B., jean-loup.bascands{at}inserm.fr; J.P.S., joost-peter.schanstra{at}inserm.fr

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., Gonzalez, J., Duchene, J., Esposito, L., Pradère, J. P., Neau, E., Delage, C., Calise, D., Ahluwalia, A., Carayon, P., Pesquero, J. B., Bader, M., Schanstra, J. P., Bascands, J. L. Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy.

Key Words: kidney disease • bradykinin • unilateral ureteral obstruction • chemokine • reversion

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