Abstract: TH-PO099
C-Terminal Binding Protein 2 (CtBP2), a NADH-Dependent Transcription Regulator Contributes to Renal Cell Dysfunction and AKI
Session Information
- AKI: Inflammation, New Technologies, Omics
October 25, 2018 | Location: Exhibit Hall, San Diego 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
Worldwide, acute kidney injury (AKI) occurs in more than 13 million patients annually. AKI is associated with high short-term morbidity, a long-term risk of chronic kidney disease (CKD) as well as adverse cardiovascular events. Mechanistically, renal tubular cell dysfunction and cell death is the hallmark and the underlying cause of AKI. However, the transcriptional regulators that control shifts in epithelial cell gene expression that triggers renal tubular cell death and dysfunction remain underexplored. Here we have examined the role of NADH-dependent transcription regulator C-terminal binding protein 2 (CtBP2) in the pathogenesis of AKI.
Methods
We have used three AKI-associated mouse models, namely cisplatin nephrotoxicity (30 mg/kg, i.p.), rhabdomyolysis (50% glycerol, 7.5 ml/kg, i.m.) and ischemia reperfusion injury (30 bilateral ischemia) and determined the mRNA and protein expression of CtBP2 during kidney injury. Furthermore, we have examined the effect of CtBP2 inhibition on AKI by using a pharmacological inhibitor (MTOB) and CtBP2-specific siRNA knockdown (hydrodynamic intravenous injection). Finally, to uncover the associated mechanisms, we carried out chromatin-immuno-precipitation (ChIP) experiments and gene expression analysis to identify CtBP2 target genes in renal epithelial cells.
Results
Renal protein expression analysis showed that CtBP2 levels are very low in normal murine kidneys. However during the early phase of cisplatin, ischemia or rhabdomyolysis induced AKI, there is a striking increase in CtBP2 protein expression in renal epithelial cells. Functional in vivo studies showed that pharmacological or genetic inhibition of CtBP2 function significantly mitigates renal impairment (BUN, Serum Creatinine and renal damage score, Control vs. CtBP2 inhibition group, p>0.05) in all the three mouse models of AKI. Through ChIP and RNA expression analysis, we have identified a CtBP2 target gene expression signature that likely contributes to renal dysfunction associated with AKI.
Conclusion
Here we have identified CtBP2 as an essential regulator of renal dysfunction and AKI. Future development of CtBP2 targeting small molecules could provide a therapeutic strategy for the prevention or treatment of AKI.
Funding
- Private Foundation Support