Histone deacetylase 4 mediates high glucose-induced podocyte apoptosis via upregulation of calcineurin.

Abstract Hyperglycemia promotes podocyte apoptosis and plays an important role in the pathogenesis of diabetic nephropathy (DN). Calcium/calcineurin (CaN) signaling is critical for podocyte apoptosis. Therefore, it is essential to elucidate the mechanisms underlying the regulation of CaN signaling. Recent studies reported that histone deacetylase 4 (HDAC4) is involved in podocyte apoptosis in DN. The aim of this study was to determine whether HDAC4 mediates the regulation of CaN and to elucidate the function of HDAC4 in high glucose (HG)-induced podocyte apoptosis. First, we identified the expression of HDAC4 was upregulated in podocytes of patients with DN. In vitro, the results also indicate that the mRNA and protein expression levels of HDAC4 were increased in HG-cultured podocytes. Silencing and overexpression of HDAC4 markedly decreased and increased CaN expression, respectively. Meanwhile, HG-induced podocyte apoptosis was abrogated by HDAC4-knockdown with subsequent decreased Bax expression and increased Bcl-2 expression. In contrast, overexpression of HDAC4 increased podocyte apoptosis and Bax expression, as well as decreased Bcl-2 expression. In addition, podocyte apoptosis induced by HDAC4 overexpression was effectively rescued by FK506, a pharmacological inhibitor of CaN, which was accompanied by decreased Bax and increased Bcl-2 expression. As a novel finding, HG-induced podocyte apoptosis is mediated by the HDAC4/CaN signaling pathway, which presents a promising target for therapeutic intervention in DN.