Journal
KIDNEY INTERNATIONAL
Volume 86, Issue 4, Pages 712-725Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2014.111
Keywords
autophagy; diabetic complications; gene therapy; histone deacetylases; podocyte
Categories
Funding
- National 973 Basic Research Program of China [2012CB517700]
- National Nature Science Foundation of China [81170772, 81328006, 81200529, 81200610]
- Shandong Natural Science Fund for Distinguished Young Scholars [JQ201121]
- Foundation of Program for New Century Excellent Talents in University [NCET-11-0311]
- Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) [IRT13028]
- Independent Innovation Foundation of Shandong University (IIFSDU) [2014JC027]
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Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-beta (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.
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