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LPA₁ Receptor Activation Promotes Renal Interstitial Fibrosis

Jean-Philippe Pradère^*,, Julie Klein^,, Sandra Grès^*,, Charlotte Guigné^*,, Eric Neau^,, Philippe Valet^*,, Denis Calise, Jerold Chun^||, Jean-Loup Bascands^,, Jean-Sébastien Saulnier-Blache^*, and Joost P. Schanstra^,

^* Inserm, U858/I2MR, Department of Metabolism and Obesity, Team 3, and Department of Renal and Cardiac Remodeling, Team 5; Université Toulouse III Paul Sabatier, Institut de Médecine Moléculaire de Rangueil; Zootechny Department IFR31, Institut Louis Bugnard, Toulouse, France; ^|| Department of Molecular Biology Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute The Scripps Research Institute, La Jolla, California

Correspondence: Dr. Joost Schanstra, Inserm, U858/I2MR, Department of Renal and Cardiac Remodeling, Team #5, 1 Avenue Jean Poulhès, BP 84225, 31432 Toulouse, Cedex 4, France. Phone: +33-5-6132-3748; Fax: +33-5-6217-2554; E-mail: schans{at}toulouse.inserm.fr

Received for publication February 13, 2007. Accepted for publication July 6, 2007.

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 LPA₁ receptor subtype, downregulation of LPA₃, and no change of LPA₂ or LPA₄. TIF was significantly attenuated in LPA₁ (–/–) 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 LPA₁ 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 LPA₁, is involved in obstruction-induced TIF. Therefore, the LPA₁ receptor might be a pharmaceutical target to treat renal fibrosis.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673