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LPA 1 Receptor Antagonists Exhibit Signaling Bias and Differential Efficacy in Models of Renal Fibrosis
Author(s) -
Hazelwood Lisa A,
Leys Laura,
Lundgaard Greta,
Putman C. Brent,
McGaraughty Steve,
Clapham Bruce,
DeGoey David,
Lee Lance
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.931.12
Subject(s) - lysophosphatidic acid , receptor , fibrosis , inflammation , signal transduction , pharmacology , microbiology and biotechnology , antagonist , cell signaling , biology , cancer research , chemistry , medicine
The endogenous phospholipid, lysophosphatidic acid (LPA), is known to mediate an array of physiologic processes, including proliferation and cell migration. In addition, LPA signaling is implicated in the pathophysiology of fibrotic disease and evokes a pro‐inflammatory response. The various effects of LPA are mediated by interaction with one of six cognate receptors, termed LPA 1–6 . In particular, many of the pro‐fibrotic and pro‐inflammatory effects of LPA are attributed to interaction with the LPA 1 receptor. LPA 1 receptor stimulation promotes signaling through G q , G i/o , G 12/13 and arrestin. Notably, while LPA species 18:1 is equipotent at evoking each of these downstream signals, we identified antagonists that exhibit biased inhibition of the various pathways. To better understand the molecular pharmacology of LPA signaling in renal fibrosis and inflammation, we studied the signaling pathways activated by 18:1 LPA in various primary human renal cell types, including proximal tubule epithelial cells and renal fibroblasts. These studies enabled mapping of the complex LPA signaling network that drives key pro‐fibrotic and pro‐inflammatory endpoints. Finally, we will present efficacy data comparing full antagonists against antagonists with various biased profiles in the mouse UUO model of renal fibrosis. In total, these data demonstrate the complexity of the LPA‐LPA 1 signaling events that drive renal fibrosis, and highlight the requisite antagonist profiles to reverse renal fibrosis endpoints in vivo. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Support or Funding Information All research was funded by AbbVie Inc.