LPA1 Receptor Antagonists Exhibit Signaling Bias and Differential Efficacy in Models of Renal Fibrosis

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 LPA1–6. In particular, many of the pro-fibrotic and pro-inflammatory effects of LPA are attributed to interaction with the LPA1 receptor. LPA1 receptor stimulation promotes signaling through Gq, Gi/o, G12/13 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 ...