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

Sun,Xinyi; Sun,Yuman; Lin,Sitong; Xu,Yan; Zhao,Dongming

doi:10.3892/mmr.2020.11496

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

Authors:
- Xinyi Sun
- Yuman Sun
- Sitong Lin
- Yan Xu
- Dongming Zhao
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Affiliations: Endocrine Department, Affiliated Hospital of Beihua University, Chuanying, Jilin 132011, P.R. China, Cardiovascular Department, Affiliated Hospital of Beihua University, Chuanying, Jilin 132011, P.R. China
Published online on: September 7, 2020 https://doi.org/10.3892/mmr.2020.11496
Pages: 4041-4047

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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.

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