Abstract: TH-PO242

Temporal Changes in Histone Deacetylases after Renal Ischemia/Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Hyndman, Kelly A., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Kasztan, Malgorzata, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Histone deacetylases (HDACs) are epigenetic regulators of transcription through deacetylation of histone lysines. Increased HDAC activity causes uncontrolled proliferation, inflammation, and/or fibrosis. Moderate ischemia/reperfusion (IR) of the kidney results in an immediate decline of renal function and injury including fibrosis followed by a stage of repair and improvement of renal function. The aim of this study was to determine if renal HDACs are dysfunctional during injury and repair after IR.

Methods

Male and female 10 week old mice underwent sham or bilateral ischemia for 27 minutes, followed by reperfusion for 1, 24, 48 or 72 h.

Results

Abnormal tubular morphology and reduced nuclei number were evident after 1 h, followed by significant reduction by 24-48 h, and reappearance of larger nuclei by 72 h. Western blots of cortical samples showed the following effects of IR on class I HDACs compared to sham: HDAC1 was increased 2.5-fold by 48 h, HDAC2 was not affected, HDAC3 initially increased 50% but returned to sham levels by 48 h, and HDAC8 was significantly reduced 40% over the study period. The class II HDAC4 was significantly increased 4-fold over the study period. To determine if the increase in HDAC promoted renal damage and fibrosis, we delivered a class I inhibitor (MS275, 20 mg/kg/day) or a class I/II inhibitor (trichostatin A, TSA, 1 mg/kg/day) by i.p. osmotic minipump 3 days prior IR. In both sexes, plasma creatinine was 2-3-fold greater in MS275 and TSA mice compared to vehicle, suggesting that inhibition of HDACs during IR results in a worsening of renal function. Histological analyses revealed reduced fibrosis in the MS275 and TSA mice, however there was an increase in protein casts in these groups. In vitro studies in primary and immortalized proximal tubular (PT) cells determined that only class I/II inhibitors led to reduced proliferation. Overexpression of HDAC4, but not HDAC1, resulted in 55% greater PT proliferation.

Conclusion

From this study, we conclude that class I and II HDACs are significantly affected during IR and display isoform specific expression patterns. Our data suggest that class I HDACs may promote fibrosis, while class II HDACs, likely HDAC4, are critical for PT proliferation and repair.

Funding

  • NIDDK Support