Received February 13, 2007
Accepted on July 6, 2007

BASIC RESEARCH: Basic Research

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 ¹

*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

¹ To whom correspondence should be addressed. E-mail: schans{at}toulouse.inserm.fr.

	Abstract

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.