Podocyte histone deacetylase activity inhibition as a therapeutic strategy for glomerular disease.

The integrity of glomerular podocytes is central to the pathogenesis of proteinuric kidney disease, but the mechanisms underlying podocyte injury remain poorly understood. Despite compelling evidence identifying the podocyte as the key injury mediator, cell-specific therapies are not clinically available, and validated therapeutic targets are scarce. Histone deacetylases (HDACs) are an evolutionarily conserved family of ubiquitously expressed proteins that are involved in multiple fundamental processes, from embryological development to disease pathogenesis, including progressive kidney disease and fibrosis. 1 Chen S. Bellew C. Yao X. et al. Histone deacetylase (HDAC) activity is critical for embryonic kidney gene expression, growth, and differentiation. J Biol Chem. 2011; 286: 32775-32789 Crossref PubMed Scopus (74) Google Scholar , 2 Liu N. He S. Ma L. et al. Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling. PLoS One. 2013; 8e54001 Crossref PubMed Scopus (132) Google Scholar In a recent study in the Journal of Clinical Investigation, Inoue et al.3 Inoue K. Gan G. Ciarleglio M. et al. Podocyte histone deacetylase activity regulates murine and human glomerular diseases. J Clin Invest. 2019; 129: 1295-1313 Crossref Scopus (32) Google Scholar identified HDAC-mediated mechanisms underlying the pathogenesis of proteinuric kidney disease and, importantly, demonstrated that modulation of this pathway improved markers of kidney function.