The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China; Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
Biochem Biophys Res Commun. 2020 Dec 17;533(4):1061-1068. doi: 10.1016/j.bbrc.2020.09.121. Epub 2020 Oct 2.
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.
高血糖促进足细胞凋亡，并在糖尿病肾病 (DN) 的发病机制中发挥重要作用。钙/钙调神经磷酸酶 (CaN) 信号对于足细胞凋亡至关重要。因此，阐明调节 CaN 信号的机制至关重要。最近的研究报道组蛋白去乙酰化酶 4 (HDAC4) 参与了 DN 中的足细胞凋亡。本研究旨在确定 HDAC4 是否介导 CaN 的调节，并阐明 HDAC4 在高糖 (HG) 诱导的足细胞凋亡中的作用。首先，我们确定了 HDAC4 在 DN 患者的足细胞中表达上调。在体外，结果还表明 HDAC4 的 mRNA 和蛋白表达水平在 HG 培养的足细胞中增加。HDAC4 的沉默和过表达分别显著降低和增加 CaN 的表达。同时，HDAC4 敲低可减轻 HG 诱导的足细胞凋亡，随后 Bax 表达降低，Bcl-2 表达增加。相反，HDAC4 的过表达增加了足细胞凋亡和 Bax 表达，同时降低了 Bcl-2 表达。此外，HDAC4 过表达诱导的足细胞凋亡可被 FK506（CaN 的药理学抑制剂）有效挽救，同时 Bax 表达降低，Bcl-2 表达增加。作为一项新发现，HG 诱导的足细胞凋亡是由 HDAC4/CaN 信号通路介导的，这为 DN 的治疗干预提供了一个有前途的靶点。
