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

Abstract

Renal fibrosis is the common histological feature of advanced glomerular and tubulointersti‐tial disease leading to end‐stage renal disease (ESRD). However' specific antifibrotic therapies to slow down the evolution to ESRD are still absent. Because persis‐tent 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 non‐peptide 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., Pradere, J. P., Neau, E., Delage, C., Calise, D., Ahluwalia, A., Carayon, P., Pesquero, J. B., Bader, M., Schanstra, J. P., Bas‐cands, J. L. Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy. FASEBJ. 23′ 134‐142 (2009)

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

“…21 We Figure 6C) mRNA expression, three chemokines known to be involved in the inflammatory process. [22][23][24] We observed that delayed B1Ra treatment blunted NTS-induced chemokine upregulation ( Figure 6).…”

“…This was associated with reduced tubulointerstitial fibrosis. 21 The promising results obtained using the UUO model led us to study the role and the therapeutic potential of the B1R in glomerulonephritides.…”

New topics in bradykinin research

“…Consequently, all markers of fibrosis (collagen, macrophages and myofibroblasts) were improved in ko-B 1 animals relative to wt. These findings could be reproduced using a B 1 agonist, demonstrating pharmacotherapeutic potential, whereas ko-B 2 , or pharmacological B 2 antagonism in wt animals, was associated with elevated renal fibrosis, indicating that B 1 receptors aggravate while B 2 receptors protect against renal fibrosis (26,27). Other studies suggest the B 1 receptor may adversely regulate energy balance by influencing leptin signalling; B 1 receptor ko animals administered a high-fat diet showed inhibition of weight gain, improved lipid oxidation, reduced food intake and increased leptin sensitivity.…”

“…Icatibant (B 2 antagonist) or des-Arg 10 -icatibant (B 1 antagonist) reduced induction of RVP by 67% and 45%, respectively, possibly preventing sight loss (82). B 1 receptor antagonists have also been shown to reduce glomerular filtration (27) and increase tumour permeability (gliomas), which could feasibly inhibit the metabolism and clearance of cytostatic agents allowing greater entry of cytostatic agent into tumours. B 2 receptor stimulation by bradykinin may promote NO-induced vasoprotective effects, including thrombin inhibition and contributing to preconditioning to protect against ischaemia.…”

La fibrose tubulo-interstitielle rénale

“…En activant le RB2, les kinines limitent le développement de la FTI car elles stimulent l'activité des protéases dégradant la MEC (Figure 3) [28]. À l'inverse, via l'activation du RB1, elles stimulent la progression de la FTI en favorisant l'expression des chimiokines par les cellules rénales lésées et le recrutement macrophagique (Figure 3) [29,30]. Bien qu'indispensables, les ARA2 et les IEC ne font que ralentir l'évolution de la fibrose sans la stopper.…”