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

Rahul Rai, Suresh K. Verma, David Kim, Veronica Ramirez, Elizabeth Lux, Chengjin Li, Susmita Sahoo, Lisa D. Wilsbacher, Douglas E. Vaughan, Susan E. Quaggin, Asish K. Ghosh*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1004-1013
Number of pages10
JournalEpigenetics
Volume12
Issue number11
DOIs
StatePublished - Nov 2 2017

Fingerprint

Fibrosis
Hypertension
Kidney
Podocytes
Mesangial Cells
Epigenomics
Fibroblasts
Intrinsic Factor
Acetyltransferases
Myofibroblasts
Cardiomegaly
Acetylation
Histones
Renal Insufficiency
Collagen
Therapeutics
Cell Proliferation
p300-CBP-associated factor
Pharmacology
Pathology

Keywords

  • Acetyltransferase p300
  • Angiotensin II
  • Cardiac Fibrosis
  • Epigenetics
  • Fibroblasts
  • Hypertension
  • Podocytes
  • Renal Fibrosis
  • Small molecule inhibitors
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Rai, Rahul ; Verma, Suresh K. ; Kim, David ; Ramirez, Veronica ; Lux, Elizabeth ; Li, Chengjin ; Sahoo, Susmita ; Wilsbacher, Lisa D. ; Vaughan, Douglas E. ; Quaggin, Susan E. ; Ghosh, Asish K. / A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis. In: Epigenetics. 2017 ; Vol. 12, No. 11. pp. 1004-1013.
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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.",
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A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis. / Rai, Rahul; Verma, Suresh K.; Kim, David; Ramirez, Veronica; Lux, Elizabeth; Li, Chengjin; Sahoo, Susmita; Wilsbacher, Lisa D.; Vaughan, Douglas E.; Quaggin, Susan E.; Ghosh, Asish K.

In: Epigenetics, Vol. 12, No. 11, 02.11.2017, p. 1004-1013.

Research output: Contribution to journalArticle

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T1 - A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis

AU - Rai, Rahul

AU - Verma, Suresh K.

AU - Kim, David

AU - Ramirez, Veronica

AU - Lux, Elizabeth

AU - Li, Chengjin

AU - Sahoo, Susmita

AU - Wilsbacher, Lisa D.

AU - Vaughan, Douglas E.

AU - Quaggin, Susan E.

AU - Ghosh, Asish K.

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

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KW - Epigenetics

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KW - Podocytes

KW - Renal Fibrosis

KW - Small molecule inhibitors

KW - TGF-β

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