Histone Deacetylases Take Center Stage on Regulation of Podocyte Function

Abstract

Background: Podocytes (highly specialized and terminally differentiated epithelial cells) are integral components of the glomerular filtration barrier that are vulnerable to a variety of injuries and, as a result, they undergo a series of changes ranging from hypertrophy to detachment and apoptosis. Podocyte injury is a major determinant in proteinuric kidney disease and identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Although numerous studies have achieved dramatic advances in the understanding of podocyte biology and its relevance to renal injury, few effective and specific therapies are available.

Summary: Epigenetic modifications have been proven to play important roles in the pathogenesis of kidney diseases. Among them, histone deacetylase (HDAC)-mediated epigenetic acetylation in the kidney has attracted much attention, which may play multiple roles in both kidney development and the pathogenesis of kidney disease. Recent studies have demonstrated that HDAC protect against podocyte injury by regulation of inflammation, apoptosis, autophagy, mitochondrial function, and insulin resistance. In this review, we summarize recent advances in the understanding of the functions and regulatory mechanisms of HDAC in podocytes and associated proteinuric kidney diseases. In addition, we provide evidence of the potential therapeutic effects of HDAC inhibitors for proteinuric kidney disease.

Key messages: Pharmacological targeting of HDAC-mediated epigenetic processes may open new therapeutic avenues for chronic kidney disease.

Keywords: Epigenetic; Histone deacetylase; Podocytes; Proteinuric kidney diseases.

Fig. 1

Structure of HDAC. The family of HDAC consists of at least 18 members, which are grouped into 4 classes, i.e., classes I, II, III, and IV. Class I HDAC (HDAC1, 2, 3, and 8), class II HDAC (HDAC4–7, 9, and 10), and class IV (HDAC11) are Zn²⁺-dependent deacetylases. The class III HDAC (also known as the Sirtuins) are composed of 7 isoforms, i.e., Sirt1 to Sirt7. aa, amino acids.

Fig. 2

a Mechanisms of Zn²⁺-dependent HDACs in podocyte injury. The activation of HDAC induces podocyte injury by regulation of EGR1. Moreover, upregulation of HDAC4 decreases autophagy to mitigate podocyte injury by upregulating the acetylated level of STAT1. MiR-29a signaling accelerates podocyte apoptosis, proteinuria, and renal fibrosis through promotion of HDAC4-dependent effects, which negatively regulates the expression of miR-29a via deacetylation of H3K9. In addition, HDAC7 can reduce KLF4 expression by downregulating the H3K9ac level in the KLF4 promoter, resulting in podocyte developmental toxicity induced by PCE in male offspring rats. b Effects of deacetylation on histone mediated by Sirts in podocytes. Under normal conditions, Sirts could deacetylate the histone and then inhibit gene transcription. However, protein levels of Sirt1 and Sirt6 are downregulated in podocyte injury, and transcription is activated. For example, the decrease in Sirt1 enhances the level of histone acetylation on H3 and H4, leading to a reduction in histone methylation of H3K9, which then promotes Claudin-1 transcription and ultimately causes podocyte injury. In addition, Sirt6 protects against podocyte injury and proteinuria in DN and focal segmental glomerulosclerosis, at least in part through epigenetic regulation of Notch signaling via binding to their promoters and deacetylating H3K9. c Effects of deacetylation on nonhistone mediated by Sirts in podocytes. Sirt1 regulates deacetylation of PGC-1α and cortactin and then improves mitochondrial function and maintains the cytoskeleton. Moreover, Sirt1 could also deacetylate FOXO3, FOXO4, p65 NF-κB, and STAT3, followed by attenuation of podocyte injury via anti-inflammation, antiapoptosis, reduction of oxidative stress, and inhibition of senescence. In addition, recent studies have demonstrated that colocalization of Sirt3 and KLF15 leads to deacetylation of KLF15, with decreased expression of fibrosis factors in podocytes with AngII treatment.