BASIC RESEARCH

LPA₁ Receptor Activation Promotes Renal Interstitial Fibrosis

Prade[Combining Grave Accent]re, Jean-Philippe^{*, †}; Klein, Julie^{† , ‡}; Gre[Combining Grave Accent]s, Sandra^{*, †}; Guigne[Combining Acute Accent], Charlotte^{*, †}; Neau, Eric^{† , ‡}; Valet, Philippe^{*, †}; Calise, Denis^§; Chun, Jerold^‖; Bascands, Jean-Loup^{† , ‡}; Saulnier-Blache, Jean-Se[Combining Acute Accent]bastien^{*, †}; Schanstra, Joost P.^{† , ‡}

Author Information

^*Inserm, U858/I2MR, Department of Metabolism and Obesity, Team 3, and ^‡Department of Renal and Cardiac Remodeling, Team 5; ^†Universite[Combining Acute Accent] Toulouse III Paul Sabatier, Institut de Me[Combining Acute Accent]decine Mole[Combining Acute Accent]culaire 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 Poulhe[Combining Grave Accent]s, BP 84225, 31432 Toulouse, Cedex 4, France. Phone: +33-5-6132-3748; Fax: +33-5-6217-2554; E-mail: [email protected]

Accepted July 6, 2007

Received February 13, 2007

Journal of the American Society of Nephrology 18(12):p 3110-3118, December 2007. | DOI: 10.1681/ASN.2007020196

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, α-smooth muscle actin (α-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 β (TGFβ). 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.