The Role Of HDAC4-induced FOXO1 Deacetylation In The Pathogenesis Of Diabetic Nephropathy

Diabetic nephropathy is the most paradigmatic example of diabetic complication, and one of the largest single cause of end-stage renal disease. So the pathogenesis of diabetic nephropathy is the focus of many scientific researchers. The pathogenesis of diabetic nephropathy has been intensely investigated, to date substantial studies have proved that various pathogenicmechanisms are involved in diabetic renal injury, including polyol pathway activation, renin-angiotensin system activation, reactive oxygen species (ROS), and activation of the protein kinase C pathway, inflammation infiltration.HDACs are a group conservative protein enzymes. They regulate chromosome structure and gene expression by maintaining the balance of acetylation and deacetylation of histones, and have close relationship with migration, differentiation of cell, cell proliferation, apoptosis and inflammatory reaction. Podocytes are renal inherent cells, a component of the glomerular filtration membrane, and influence glomerular filtration rate. The lack of podocytes has become a typical early event of diabetic nephropathy. In the present study, we used an in vivo STZ-induced diabetic model, renal biopsies from DN patients and in vitro podocyte cultures to determine the expression and roles of HDAC4 in diabetic nephropathy. Our results exhibited that there are incrassation of basement membrane, the fusion of foot processes in podocytes, inflammation infiltration and damage of glomerular podocye continuity in STZ-induced DN rats. By Western blot, immunofluorescence and immunohistochemistry analyses, it was found that that HDAC4 were detected in the normal kidney, was significantly increased in the renal from STZ-induced DN rats, and these results were further confirmed in renal biopsies of DN patients. In in vitro study, HDAC4 was upregulated in response to high glucose in podocytes. By co-immunoprecipition analyses, high glucose increased the interaction of HDAC4 and FOXO1. In addition, high glucose and HDAC4 affected the acetylation level of FOXO1. Moreover, by flow cytometry and Western blot analyses, high glucose, the level of HDAC4 and FOXO1 affected podocyte apoptosis and expression of apoptosis-related genes. The upregulation expression of HDAC4 in diabetic nephropathy model reveals that HDAC4 may participate in development and progression of diabetic nephropathy. And HDAC4 is involved in the regulation of podocyte apoptosis by a signal transduction that links FOXO1-Bim2 response to apoptosis.