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Abstract: FR-OR035

The Role of HDAC Activation in Proteinuric Kidney Disease Progression in Mice and Humans

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Inoue, Kazunori, Yale University School of Medicine, New Haven, Connecticut, United States
  • Parikh, Chirag R., Yale University School of Medicine, New Haven, Connecticut, United States
  • Wilson, Francis Perry, Yale University School of Medicine, New Haven, Connecticut, United States
  • Ishibe, Shuta, Yale University School of Medicine, New Haven, Connecticut, United States
Background

As the incidence and prevalence of End Stage Kidney Disease due to proteinuric diseases continue to rise, alternative novel therapies are required.

Methods

An adult-onset proteinuric disease model was generated using doxycycline (DOX)-induced podocyte specific Talin1 knockout (iTln1 KO) mice. Our findings were validated using podocyte specific germline Dynamin1 and 2 KO (Dnm DKO) and Tln1 KO mice treated with 2 different histone deacetylase (HDAC) inhibitors (valproic acid (VPA) and vorinostat (SAHA)). We generated DOX-induced podocyte specific Hdac1 and 2 KO or early growth response 1 (Egr1) KO mice. Microarray was performed from isolated glomeruli in control and the iTln1 KO mice +/- VPA to unearth differentially expressed genes (DEGs). HDAC1 and 2 activities were measured using an activity assay kit. For in-vitro podocyte injury models, lipopolysaccharide (LPS) or protamine sulfate (PS) were used. Observational data in patients on VPA in the Veterans Aging Cohort Study (VACS) was analyzed for estimated glomerular filtration rate (eGFR).

Results

Using Connectivity Map database and Drug Pair Seeker, Hdac1 and 2 genes and HDAC inhibitors were identified as potential targets regulating or reversing the 188 DEGs in control vs iTln1 KO mice glomeruli. Deletion of podocyte Hdac1 and 2, in iTln1 KO mice where podocyte HDAC1 and 2 are activated, and treatment with VPA, or SAHA ameliorated progression of proteinuria and kidney failure in these mice. VPA also improved survival in Dnm DKO and Tln1 KO mice that die from kidney failure (Dnm DKO:35 (median survival (days)), Dnm DKO+VPA:77.5, Tln1 KO:30.5, and Tln1 KO+VPA:64). From our RNA profiling data, we also identified Egr1 as a potential VPA regulated target. Loss of Egr1 in iTln1 KO mice mitigated proteinuria and kidney failure (control:0.11 +/- 0.02 (plasma creatinine (mg/dl)), iTln1 KO:0.35 +/- 0.02, Egr1, iTln1 DKO:0.19 +/- 0.02). Egr1 KO podocytes stabilized the actin cytoskeleton following LPS or PS in vitro. Longitudinal analysis of VACS revealed reduction in the mean annual eGFR loss among those receiving VPA (-0.48 (ml/year) in VPA user vs -1.10 in non VPA user).

Conclusion

Our results demonstrate inhibition of HDAC1 and 2 activation not only improved proteinuric mice models but also suggests a novel therapeutic strategy in progressive proteinuric human kidney diseases.