Back to Search
Start Over
Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish
- Source :
- Disease Models & Mechanisms, Disease Models & Mechanisms, Vol 12, Iss 4 (2019)
- Publication Year :
- 2019
- Publisher :
- The Company of Biologists Ltd, 2019.
-
Abstract
- 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 Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 (Kim-1) expression, and lowers the number of infiltrating macrophages. Further, we found that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate that the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic. This article has an associated First Person interview with the joint first authors of the paper.<br />Summary: Mortality associated with AKI is in part due to limited treatments available to ameliorate injury. The authors identify a compound that accelerates AKI recovery and promotes cellular dedifferentiation.
- Subjects :
- 0301 basic medicine
Cellular Dedifferentiation
Neutrophils
030232 urology & nephrology
Medicine (miscellaneous)
lcsh:Medicine
Cardiovascular
Animals, Genetically Modified
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
Fibrosis
Prodrugs
Zebrafish
Kidney
biology
Histone deacetylase inhibitor
Acute kidney injury
Acute Kidney Injury
3. Good health
Butyrates
medicine.anatomical_structure
Kidney Tubules
Therapeutic
lcsh:RB1-214
Research Article
Signal Transduction
medicine.drug_class
Neuroscience (miscellaneous)
Renal proximal tubule cell
Tretinoin
Sulfides
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
HDAC inhibitor
medicine
Renal fibrosis
lcsh:Pathology
Animals
Regeneration
Cell Proliferation
business.industry
Regeneration (biology)
Macrophages
lcsh:R
PAX2 Transcription Factor
Epithelial Cells
Cell Dedifferentiation
Zebrafish Proteins
medicine.disease
biology.organism_classification
Zebra
030104 developmental biology
Immune System
Cancer research
business
Subjects
Details
- Language :
- English
- ISSN :
- 17548411 and 17548403
- Volume :
- 12
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....32200babf698ae21c15fe3626d144dae