Histone deacetylase inhibitor valproic acid attenuates high glucose‑induced endoplasmic reticulum stress and apoptosis in NRK‑52E cells

Abstract

Previous studies have demonstrated that valproic acid (VPa), a histone deacetylase inhibitor, alleviates diabetic nephropathy (dn). However, the biological mechanisms underlying this protective effect remains unclear. This study aimed to investigate the effects of histone deacetylase inhibitor VPa on hyperglycemic induction of nrK-52e cell erS and apoptosis. endoplasmic reticulum stress (erS)-related apoptosis is involved in dn, and improving erS may delay the symptoms of dn. Histone deacetylase regulates gene transcription or expression of erS-related proteins. The present study established an erS model by treating the rat renal tubular epithelial cells nrK-52e with high glucose (HG) and investigated the effects of VPa on the apoptosis of the nrK-52e cells. HG stimulation significantly increased the protein levels of the ERS-related proteins including glucose regulated protein 78 (GrP78), activating transcription factor 4 (aTF4), c/eBP homologous protein (cHoP), caspase-12 and phosphorylated (p)-JnK. VPa treatment further upregulated GrP78 expression and attenuated the levels of aTF4, cHoP, caspase-12 and p-JnK. notably, HG markedly promoted apoptosis of nrK-52e cells by regulating the protein levels of Bax, cleaved caspase-3 and Bcl-2, which was attenuated by simultaneous VPa treatment. Mechanistically, VPa increased the total acetylation levels of histone H4 in nrK-52e cells and increased the histone H4 acetylation of the GrP78 promoter region. in conclusion, VPa attenuated HG-induced erS and apoptosis in nrK-52e cells, which may be due to the regulation of acetylation levels of erS-related proteins. in addition, the present study suggested that Hdacis are promising drugs for treating patients with dn.

Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression

“…4-PBA is generally used to treat urea cycle disorders, however, it is also a low molecular weight chemical chaperone that prevents misfolded protein aggregation and mitigates ER stress 42 . VPA is also known to alleviate ER stress triggered by a broad spectrum of stressors 43 , 44 . Here, we have demonstrated that HIER stress cannot be resolved neither by 4-PBA nor by VPA, on the contrary, ECs showed increased sensitivity towards HIER stress characterized by greater CHOP activation because of diminished HO-1 expression in 4-PBA and VPA-treated cells.…”

Histone deacetylase‐mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy‐induced PANoptosis

“…Histone deacetylases (HDACs) are enzymes that remove acetyl groups from specific lysine residues on cellular and DNA binding proteins, such as histones, to regulate protein function, chromatin architecture and gene expression (Jin et al, 2023). Recent studies in several animal models suggest that HDAC inhibitors can protect against diabetic nephropathy (Sun et al, 2020), suppress kidney fibrosis in a unilateral ureteral ligation model (Liu et al, 2013), enhance kidney recovery from acute kidney injury (Brilli Skvarca et al, 2019) and HDAC inhibitor administration resulted in kidney protection that was associated with reductions in inflammation and programmed cell death (Yusoff et al, 2019). Yao et al provided evidence that histone deacetylase 11 (HDAC11) promotes NOD-like receptor protein 3 (NLRP3)/caspase 1/gasdermin D (GSDMD) and caspase 3/gasdermin E (GSDME) pathways, leading to vascular endothelial cell pyroptosis (Yao et al, 2022).…”

Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues

“…The majority of people suffer from type 2 diabetes mellitus (T2DM), where changes in insulin production, secretion, and /or function change the uptake and clearance of glucose from the bloodstream and contribute to the development of T2DM. Chronic hyperglycemia that is not arrested and controlled due to impaired beta cell differentiation, proliferation and secretory dysfunction, which fail to compensate for insulin resistance, leads to microvascular complications such as end-stage renal disease (ESRD), kidney failure, and diabetic nephropathy [ 2 ], as well as inflammation of the retinal blood vessels of the eye, which leads to vision loss and diabetic retinopathy [ 3 ]. Previous research has demonstrated that ER stress, oxidative stress, and cytokine-driven inflammatory stress are all connected to the aetiology of DM at the cellular level.…”