Abstract: SA-PO068
Whole-Genome Chromatin Immunoprecipitation Sequencing Identifies a Role of CtBP2 in Renal Cell Dysfunction and AKI
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kim, Ji Young, The Ohio State University, Columbus, Ohio, United States
- Bai, Yuntao, The Ohio State University, Columbus, Ohio, United States
- Jayne, Laura A., The Ohio State University, Columbus, Ohio, United States
- Pabla, Navjotsingh P., The Ohio State University, Columbus, Ohio, United States
Background
Acute kidney injury (AKI) is a clinical syndrome characterized by rapid decline in renal function that results in 2 million deaths annually worldwide and pays for billions of dollars in US healthcare costs. In a pathophysiologic manner, renal tubular cell dysfunction and cell death is the hallmark and the underlying cause of AKI. However, the transcriptional regulators that control alteration in epithelial cell gene expression that triggers renal tubular cell dysfunction and death remain underexplored. The application of deep transcriptional sequencing has provided the new insights of AKI. Here we have examined the role of transcription regulator C-terminal binding protein 2 (CtBP2) in the pathogenesis of AKI through global profiling.
Methods
The mRNA and protein expression of CtBP2 were determined in multiple AKI-associated mouse models, namely rhabdomyolysis, ischemia reperfusion injury, and cisplatin nephrotoxicity. To define the role of CtBP2 in vivo, a pharmacological inhibitor (MTOB) and CtBP2-specific siRNA knockdown (hydrodynamic intravenous injection) were examined in ischemia- and cisplatin- associated AKI. Finally, to directly determine the molecular targets of CtBP2, we carried out chromatin immunoprecipitation followed by sequencing (ChIP-Seq) in rhabdomyolysis-induced AKI and associated changes of the target gene expression of CtBP2 in multiple AKI-associated mouse models with RNA-sequencing (RNA-Seq) data.
Results
During the early phase of rhabdomyolysis, ischemia, and cisplatin induced AKI, there is a remarkable increase in CtBP2 protein expression in renal epithelial cells. Functional in vivo studies showed that inhibition of CtBP2 function significantly improves renal impairment in ischemia and cisplatin-associated kidney injury. Global analysis of CtBP2 in rhabdomyolysis-induced AKI revealed that it drives DNA damage, cell cycle, cell proliferation/differentiation pathway, and carbohydrate/lipid metabolism. These target genes of CtBP2 were validated by RNA-Seq and qPCR analysis in all three AKI-associated murine kidneys.
Conclusion
Here we first have identified broad roles for CtBP2 as a transcriptional repressor during acute kidney injury. We propose that development of CtBP2 targeting small molecules could provide a therapeutic strategy for the treatment of AKI.
Funding
- Private Foundation Support