Journal
KIDNEY INTERNATIONAL
Volume 79, Issue 12, Pages 1312-1321Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2011.39
Keywords
diabetes mellitus; diabetic nephropathy; epidermal growth factor; proliferation; proximal tubule
Categories
Funding
- JP Bickell Foundation
- Servier Vascular Research Award
- CIHR
- Canadian Diabetes Association
- Canada Research Chair Program
- KRESCENT
- Banting and Best Diabetes Centre, University of Toronto
- Heart and Stroke Foundation of Ontario
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Clinical trials and experimental studies have highlighted the importance of epigenetic processes in the development of diabetic complications. One of the earliest features of diabetic nephropathy is renal enlargement. The epidermal growth factor (EGF) has a pivotal role in the development of diabetic nephromegaly and transactivation of its receptor has been implicated in the pathogenesis of later-stage disease. As EGF signaling is altered by the acetylation status of histone proteins, we measured the effects of the histone deacetylase (HDAC) inhibitor, vorinostat, in mediating renal enlargement in diabetes focusing on the EGF-EGF receptor (EGFR) axis. In cultured proximal tubule (normal rat kidney) cells, vorinostat treatment reduced EGFR protein and mRNA, and attenuated cellular proliferation. Within 72 h of diabetes induction with streptozotocin, urinary EGF excretion was increased approximately threefold and was unaffected by vorinostat, even though the kidneys of vorinostat-treated diabetic rats had reduced tubular epithelial cell proliferation. Daily treatment of diabetic rats with vorinostat for 4 weeks blunted renal growth and glomerular hypertrophy. Thus, early renal changes in diabetes are amenable to epigenetic intervention. Attenuating effects of HDAC inhibition, although multifactorial, are likely to be mediated in part through downregulation of the EGFR. Kidney International (2011) 79, 1312-1321; doi:10.1038/ki.2011.39; published online 9 March 2011
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