A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis.

Academic Article

Abstract

  • Hypertension-associated end-organ damage commonly leads to cardiac and renal fibrosis. As no effective anti-fibrotic therapy currently exists, the unchecked progression of fibrogenesis manifests as cardio-renal failure and early death. We have previously shown that FATp300-p300 with intrinsic factor acetyltransferase activity-is an essential epigenetic regulator of fibrogenesis, and is elevated in several fibrotic tissues. In this report, we investigate the therapeutic efficacy of a novel FATp300 inhibitor, L002, in a murine model of hypertensive cardio-renal fibrosis. Additionally, we examine the effects of L002 on cellular pro-fibrogenic processes and provide mechanistic insights into its antifibrogenic action. Utilizing cardiac fibroblasts, podocytes, and mesangial cells, we demonstrate that L002 blunts FATp300-mediated acetylation of specific histones. Further, incubating cells with L002 suppresses several pro-fibrogenic processes including cellular proliferation, migration, myofibroblast differentiation and collagen synthesis. Importantly, systemic administration of L002 in mice reduces hypertension-associated pathological hypertrophy, cardiac fibrosis and renal fibrosis. The anti-hypertrophic and anti-fibrotic effects of L002 were independent of blood pressure regulation. Our work solidifies the role of epigenetic regulator FATp300 in fibrogenesis and establishes it as a pharmacological target for reducing pathological matrix remodeling and associated pathologies. Additionally, we discover a new therapeutic role of L002, as it ameliorates hypertension-induced cardio-renal fibrosis and antagonizes pro-fibrogenic responses in fibroblasts, podocytes and mesangial cells.

    • Authors

    Published In

  • Epigenetics  Journal

    • Keywords

  • Acetyltransferase p300, Angiotensin II, Cardiac Fibrosis, Epigenetics, Fibroblasts, Hypertension, Podocytes, Renal Fibrosis, Small molecule inhibitors, TGF-β, Animals, Cardio-Renal Syndrome, Cell Line, Cell Proliferation, Cells, Cultured, Collagen, E1A-Associated p300 Protein, Fibrosis, Histone Deacetylase Inhibitors, Humans, Hypertension, Mesangial Cells, Mice, Mice, Inbred C57BL, Myofibroblasts, Podocytes

    • Digital Object Identifier (doi)

    Author List

  • Rai R; Verma SK; Kim D; Ramirez V; Lux E; Li C; Sahoo S; Wilsbacher LD; Vaughan DE; Quaggin SE

    • Start Page

  • 1004

    • End Page

  • 1013

    • Volume

  • 12

    • Issue

  • 11