Lysophosphatidic acid signaling through its receptor initiates pro-fibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor

Abstract

The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA ₁ expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA ₁ signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA ₁-deficient (LPA _1−/−) or -sufficient (LPA _1+/+) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I pro-collagen promoter (Col-GFP) to identify fibroblasts. Unilateral ureteral obstruction-induced increases in renal collagen were significantly, though not completely, attenuated in LPA _1−/−Col-GFP mice, as were the accumulations of both fibroblasts and myofibroblasts. Connective tissue growth factor was detected mainly in tubular epithelial cells, and its levels were suppressed in LPA _{1 −/−}Col-GFP mice. LPA-LPA ₁ signaling directly induced connective tissue growth factor expression in primary proximal tubular epithelial cells, through a myocardin-related transcription factor-serum response factor pathway. Proximal tubular epithelial cell derived connective tissue growth factor mediated renal fibroblast proliferation and myofibroblast differentiation. Administration of an inhibitor of myocardin-related transcription factor/serum response factor suppressed obstruction-induced renal fibrosis. Thus, targeting LPA-LPA ₁ signaling and/or myocardin-related transcription factor/serum response factor-induced transcription could be promising therapeutic strategies for renal fibrosis.