Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Kazunori Inoue, Geliang Gan, Maria Ciarleglio, Yan Zhang, Xuefei Tian, Christopher E. Pedigo, Corey Cavanaugh, Janet Tate, Ying Wang, Elizabeth Cross, Marwin Groener, Nathan Chai, Zhen Wang, Amy Justice, Zhenhai Zhang, Chirag Parikh, Francis P. Wilson, Shuta Ishibe

Research output: Contribution to journalArticle

Abstract

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

Original languageEnglish (US)
Pages (from-to)1295-1313
Number of pages19
JournalThe Journal of clinical investigation
Volume129
Issue number3
DOIs
StatePublished - Mar 1 2019

Keywords

  • Cell Biology
  • Molecular biology
  • Nephrology

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Podocyte histone deacetylase activity regulates murine and human glomerular diseases'. Together they form a unique fingerprint.

  • Cite this

    Inoue, K., Gan, G., Ciarleglio, M., Zhang, Y., Tian, X., Pedigo, C. E., Cavanaugh, C., Tate, J., Wang, Y., Cross, E., Groener, M., Chai, N., Wang, Z., Justice, A., Zhang, Z., Parikh, C., Wilson, F. P., & Ishibe, S. (2019). Podocyte histone deacetylase activity regulates murine and human glomerular diseases. The Journal of clinical investigation, 129(3), 1295-1313. https://doi.org/10.1172/JCI124030