tretinoin and 4-(phenylthio)butanoic-acid

Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI), as an enhancer of renal recovery, and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene

Topics: Acute Kidney Injury; Animals; Animals, Genetically Modified; Butyrates; Cell Dedifferentiation; Cell Proliferation; Epithelial Cells; Immune System; Kidney Tubules; Macrophages; Neutrophils; PAX2 Transcription Factor; Prodrugs; Regeneration; Signal Transduction; Sulfides; Tretinoin; Zebrafish; Zebrafish Proteins

One of the first hallmarks of kidney regeneration is the reactivation of genes normally required during organogenesis. Identification of chemicals with the potential to enhance this reactivation could therapeutically promote kidney regeneration. Here, we found that 4-(phenylthio)butanoic acid (PTBA) expanded the expression domains of molecular markers of kidney organogenesis in zebrafish. PTBA exhibits structural and functional similarity to the histone deacetylase (HDAC) inhibitors 4-phenylbutanoic acid and trichostatin A; treatment with these HDAC inhibitors also expanded the renal progenitor cell population. Analyses in vitro and in vivo confirmed that PTBA functions as an inhibitor of HDAC activity. Furthermore, PTBA-mediated renal progenitor cell expansion required retinoic acid signaling. In summary, these results support a mechanistic link among renal progenitor cells, HDAC, and the retinoid pathway. Whether PTBA holds promise as a therapeutic agent to promote renal regeneration requires further study.

Topics: Animals; Butyrates; Cell Proliferation; Drug Evaluation, Preclinical; Embryonic Stem Cells; Histone Deacetylase Inhibitors; Kidney; Regeneration; Signal Transduction; Structure-Activity Relationship; Sulfides; Tretinoin; Zebrafish