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Kidney Week

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Abstract: PO0398

Ischemia Reperfusion Activation of Kidney HDAC1 Results in Interstitial Fibrosis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hyndman, Kelly A., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Mendoza, Luciano D., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Ramos, Ariana Sofia, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Aldaz, Kaitlyn, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
Background

Following a kidney ischemic event the chromatin remodeling enzyme, histone deacetylase-1 (HDAC1), is activated in many cell types of the kidney including fibroblasts/pericytes. Pharmacological inhibition of HDACs can attenuate ischemia-reperfusion-injury (IRI) mediated interstitial fibrosis. In this study, we tested the hypothesis that fibroblast/pericyte HDAC1 activation promotes interstitial fibrosis.

Methods

Tamoxifen inducible, fibroblast/pericyte HDAC1 knockout (KO) mice (HDAC1Fl/Fl; Col1a2-CreEr) and littermate controls (HDAC1Fl/Fl) were used. Male and female mice (8-10 wks of age) were given tamoxifen i.p. and IRI or sham surgery was performed after a 2-week tamoxifen washout period. A mild, 18 min, bilateral, warm IRI model was used and samples collected over 4 weeks. Additional groups of mice underwent unilateral ureteral obstruction (UUO) for 48 h. In vitro experiments with kidney fibroblast cells (NRK49F) overexpressing HDAC1 were used for RNA-sequencing studies.

Results

HDAC1 KO was confirmed in myofibroblast cells by co-immunolocalization of HDAC1 and platelet-derived growth factor receptor beta or a-smooth muscle actin (α-sma) in the kidneys of IRI mice. 24 h post ischemia there was a tripling of plasma creatinine (PCr) in all IRI mice, regardless of sex or genotype. 2- and 4-weeks after IRI, PCr were similar to sham values for all mice. However, the male control IRI mice had significant interstitial fibrosis but this was attenuated in the KO male IRI mice. The female mice, regardless of genotype, had very mild kidney damage and interstitial fibrosis at 4 weeks. The UUO male KO mice had reduced α-sma abundance compared to control male mice. Transcriptomes of NRK49F cells overexpressing HDAC1 had 15 genes upregulated (0.1% of the genes sequenced) and 64 genes downregulated (0.5%). Upregulated genes included C3, Bmp6, Cxcl12, and Fzd1. Downregulated genes included Ccl4, Ifnb1. Gene Ontology analysis determined significant enrichment in the regulation of Wnt signaling and innate immune response activating signal transduction.

Conclusion

For male mice, fibroblast/pericyte HDAC1 activation leads to pro-fibrotic programming of the myofibroblast and interstitial fibrosis. Future studies will determine the specific epigenetic pathways that may be significantly changed by HDAC1 activation leading to maladaptive interstitial fibrosis.

Funding

  • NIDDK Support