Targeting Histone Deacetylase in Focal Segmental Glomerulosclerosis - From Mice to Patients
Abstract
Nearly 600,000 Americans suffer from end-stage kidney disease (ESKD), a failure of kidney function that necessitates either dialysis or a kidney transplant. Medicare expenditures for ESKD exceed 28 billion dollars annually. The vast majority of ESKD in the US is due to glomerular disease -- a process in which the filtering component of the kidney is damaged, resulting in the loss of protein in the urine. Focal Segmental Glomerulosclerosis (FSGS) is the most common glomerular disease and can arise in the setting of diabetes, hypertension, or as an isolated condition. Few treatments exist for kidney diseases where excessive protein is found in the urine. Our prior research in a mouse model of FSGS revealed upregulation of a protein called histone deacetylase (HDAC), which has multiple effects on transcription of DNA. Importantly, inhibition of this protein using a commonly available medication called valproic acid (VPA) resulted in improved kidney function and increased survival in mice. We also used data from the Veterans Affairs (VA) system to identify a large population of Veterans, some of whom were exposed to VPA and some of whom weren’t. Those exposed to VPA had a significantly slower rate of loss of kidney function than those not exposed to the drug, suggesting VPA might be protective in humans. This effect was most profound in those who had the most protein in their urine, again suggesting that this drug might be beneficial for those with glomerular disease. We hypothesize that VPA, by inhibiting histone deacetylase, changes the response of the kidney to ongoing injury in a protective manner. The purpose of this grant is to determine exactly how that happens and to verify that the effect is robust in humans from multiple walks of life. The first aim of the study is to confirm the VPA effects using another HDAC inhibitor called suberanilohydroxamic acid (SAHA). The next aim will confirm that HDAC is the important factor mediating the effect of VPA by knocking this gene out of key cells in the kidney. The third aim will determine which genes are up- or downregulated by HDAC in order to better understand how the protective effect occurs. The fourth aim will examine the effect of VPA exposure in three large cohorts totaling over 4.5 million individuals, some receiving care at VA hospitals and some at a large community-based health system. Finally, the fifth aim will identify exactly which patients most strongly benefit from VPA exposure. These analyses, if successful, will lead directly to clinical trials evaluating the effect of VPA on key subsets of individuals with kidney disease, providing, for the first time in two decades, a potentially new class of weapon in the fight against ESKD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710663
Entities
People
- Francis Wilson
Organizations
- United States Army
- Yale University