Abstract
Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. YAP and TAZ have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis, but their expression in other cells is essential to regeneration and homeostasis, complicating efforts to target them in fibrotic pathologies. Here we find that the Galpha-s-coupled dopamine receptor D1 is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of the D1 receptor selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from pro-fibrotic to fibrosis-resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis. Expression of transcripts encoding DOPA decarboxylase (DDC), the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically-tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis.
Published Version
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