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4-(Phenylthio)butanoic acid, a novel histone deacetylase inhibitor, stimulates renal progenitor cell proliferation

de Groh, Eric David (2010) 4-(Phenylthio)butanoic acid, a novel histone deacetylase inhibitor, stimulates renal progenitor cell proliferation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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A chemical screen of approximately 2000 small molecules in zebrafish embryos identified a compound that generated pericardial edema, suggesting aberrant renal development. Treatment with this compound, 4-(phenylthio)butanoic acid (PTBA), increased the size of the pronephric kidney in zebrafish. Earlier in development, PTBA expanded the expression of renal progenitor cell markers, including lhx1a, pax2a, and pax8. Blocking DNA synthesis with hydroxyurea and aphidicolin before PTBA treatment decreased its efficacy, suggesting that PTBA-mediated renal progenitor expansion is proliferation dependent. Structure-activity analysis revealed that PTBA was an analog of the known histone deacetylase inhibitors (HDACis) 4-phenylbutanoic acid (PBA) and trichostatin A (TSA). Like PTBA, PBA and TSA both demonstrated the ability to expand lhx1a expression in treated embryos. PTBA was subsequently confirmed to function as an HDACi both in vitro and in vivo. HDACis are hypothesized to stimulate retinoic acid (RA) signaling by decreasing the concentration of RA necessary to activate RA receptors (RARs) on target genes. Indeed, treatment with PTBA affected the expression of the RA-responsive genes, cyp26a1 and cmlc2, in a manner consistent with increased RA signaling. Furthermore, blocking the RA pathway with a dominant-negative RAR alpha construct decreased PTBA efficiency. Therefore, PTBA appears to stimulate renal progenitor cell proliferation by activating the RA-signaling pathway. HDACis have been shown to improve renal recovery following acute kidney injury. Since PTBA increases renal progenitor cell proliferation, it may exert similar effects on the multipotent cells involved in regeneration. In an effort to improve PTBA efficacy for pharmacological applications, analogs were generated by modifying the key structural elements of the general HDACi pharmacophore. These were tested along with a panel of known HDACis for their ability to increase lhx1a expression in treated embryos. Several compounds were characterized that function at nanomolar concentrations and do not cause toxicity in kidney cell culture. These second generation PTBA analogs are excellent candidates for development as potential renal therapeutics.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
de Groh, Eric Davidedd18@pitt.eduEDD18
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHukriede, Neil Ahukriede@pitt.eduHUKRIEDE
Committee MemberRoman, Beth Lromanb@pitt.eduROMANB
Committee MemberBrodsky, Jeffrey Ljbrodsky@pitt.eduJBRODSKY
Committee MemberDavidson, Lance Alad43@pitt.eduLAD43
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Date: 21 December 2010
Date Type: Completion
Defense Date: 12 November 2010
Approval Date: 21 December 2010
Submission Date: 10 December 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Integrative Molecular Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: drug discovery; embryogenesis; kidney regeneration; kidney repair; organogenesis; pronephros; structure-activity relationship
Other ID:, etd-12102010-111218
Date Deposited: 10 Nov 2011 20:10
Last Modified: 15 Nov 2016 13:54


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