LPA1 Receptor Activation Promotes Renal Interstitial Fibrosis

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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 LPA1–4 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.