Abstract: SA-PO1179
Role of Histone Deacetylase-1 in Interstitial Fibrosis
Session Information
- NIDDK KUH Summer Undergraduate Research Program Posters
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Author
Group or Team Name
- Kaitlyn Aldaz. The University of Alabama at Birmingham, Birmingham, AL.
Background
Acute kidney injury can lead to chronic kidney disease through myofibroblast secretion of extracellular matrix (ECM) leading to interstitial fibrosis and a loss of kidney function. We reported that following ischemia-reperfusion-injury (IRI), the transcriptional regulator, histone deacetylase-1 (HDAC1) is increased in the kidney. Inhibition of HDAC1 reduced IRI-mediated interstitial fibrosis. We hypothesized that fibroblast HDAC1 was profibrotic and developed an inducible HDAC1 fibroblast knockout (KO) mouse.
Methods
Fibroblast HDAC1 was deleted in adulthood, and the male mice underwent sham or bilateral IRI (2-weeks of reperfusion) surgeries.
Results
Plasma creatinine was significantly elevated in control IRI mice (0.20 ± 0.02 mg/dl) compared to sham (0.12 ± 0.001) or KO mice (sham = 0.13 ± 0.009, IRI = 0.14 ± 0.02, PGenotype = 0.2, PSurgery = 0.02, Pinteraction = 0.03) suggesting that the KOs had better kidney function. Interstitial sirius red staining, α−smooth muscle actin (αsma), and fibronectin expression was increased in the control IRI mice compared to shams or KO mice. Next, Normal Rat Kidney 49 Fibroblast cells transfected with human HDAC1 or empty vectors. Injury was simulated by treatment of cells with TGF-β1, a master regulator of myofibroblast activation. Overexpression of HDAC1 did not significantly affect myofibroblast markers (αsma, fibronectin). TGF-β1 treatment led to myofibroblast activation, regardless of HDAC1 level. Interestingly, HDAC1 was found to suppress p53 expression, a master regulator of the cell cycle.
Conclusion
Together, our data suggest that fibroblast HDAC1 is profibrotic, but it may be through regulation of myofibroblast cell cycle, rather than direct effects on ECM secretion.