Tubulointerstitial fibrosis in chronic renal disease is strongly associated with progressive loss of renal function. We studied the potential involvement of lysophosphatidic acid (LPA), a growth factor-like phospholipid, and its receptors LPA 1-4 in the development of tubulointerstitial fibrosis (TIF). Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) for up to 8 d, and kidney explants were prepared from the distal poles to measure LPA release into conditioned media. After obstruction, the extracellular release of LPA increased approximately 3-fold. Real-time reverse transcription PCR (RT-PCR) analysis demonstrated significant upregulation in the expression of the LPA 1 receptor subtype, downregulation of LPA 3 , and no change of LPA 2 or LPA 4 . TIF was significantly attenuated in LPA 1 (Ϫ/Ϫ) mice compared to wild-type littermates, as measured by expression of collagen III, ␣-smooth muscle actin (␣-SMA), and F4/80. Furthermore, treatment of wild-type mice with the LPA 1 antagonist Ki16425 similarly reduced fibrosis and significantly attenuated renal expression of the profibrotic cytokines connective tissue growth factor (CTGF) and transforming growth factor ␤ (TGF␤). In vitro, LPA induced a rapid, dose-dependent increase in CTGF expression that was inhibited by Ki16425. In conclusion, LPA, likely acting through LPA 1 , is involved in obstruction-induced TIF. Therefore, the LPA 1 receptor might be a pharmaceutical target to treat renal fibrosis.

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Background-The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B 1 -and B 2 -receptor expression, which are the molecular entities responsible for the biological effects of kinins. Methods and Results-Rats were subjected to different 6-week treatments using various mixtures of the following agents:ACE inhibitor, angiotensin AT 1 -receptor antagonist, and B 1 -and B 2 -receptor antagonists. Chronic ACE inhibition induced both renal and vascular B 1 -receptor expression, whereas B 2 -receptor expression was not modified. Furthermore, with B 1 -receptor antagonists, it was shown that B 1 -receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B 1 -receptors in all segments. ACE-inhibitor-induced B 1 -receptor induction involved homologous upregulation, because it was prevented by B 1 -receptor antagonist treatment. Finally, using B 2 -receptor knockout mice, we showed that ACE-inhibitor-induced B 1 -receptor expression was B 2 -receptor independent. Conclusions-This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B 1 -receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B 1 -receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.

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)