LPA1 receptor activation promotes renal interstitial fibrosis.
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 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, alpha-smooth muscle actin (alpha-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 beta (TGFbeta). 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.
Pradère
Jean-Philippe
JP
Inserm, U858/I2MR, Department of Metabolism and Obesity, Team 3, Toulouse, France.
Klein
Julie
J
Grès
Sandra
S
Guigné
Charlotte
C
Neau
Eric
E
Valet
Philippe
P
Calise
Denis
D
Chun
Jerold
J
Bascands
Jean-Loup
JL
Saulnier-Blache
Jean-Sébastien
JS
Schanstra
Joost P
JP
D000818:Animals; D017077:Culture Media, Conditioned / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010743:Phospholipids / Q000737:chemistry; D011422:Propionates / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014513:Ureter / Q000196:embryology
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D017077:Culture Media, Conditioned; D007555:Isoxazoles; D008246:Lysophospholipids; D010743:Phospholipids; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D016212:Transforming Growth Factor beta; C032881:lysophosphatidic acid