Suppression of HDAC2 by sodium butyrate alleviates apoptosis of kidney cells in db/db mice and HG‑induced NRK‑52E cells

Abstract

Butyrate is short-chain fatty acid, which is produced by intestinal microbiota metabolizing dietary fibers. Butyrate participates in various physiological processes predominantly by activating G-coupled-receptors, inhibiting histone deacetylases (HDACs) and serving as an energy substrate. Previous studies have shown that butyrate plays a protective role in diabetic nephropathy (DN); however, the exact mechanism remains unclear. The present study identified that providing sodium butyrate (NaBu) by gavage relieved renal damage and apoptosis in db/db mice, which is a widely used type 2 DN model. In vitro, NaBu suppressed high glucose (HG)-induced apoptosis in normal rat kidney tubular epithelial (NRK-52E) cells. Of the eleven HDACs (HDAC1-11) studied, only the mRNA expression of HDAC2 was attenuated by NaBu in NRK-52E cells under the HG condition. Overexpression of HDAC2 offset the anti-apoptotic effect of NaBu. NaBu also suppressed HG-induced oxidative stress. Additionally, H2O2 induced an upregulation of HDAC2 in NRK-52E cells, while NaBu inhibited this process. Mechanistically, NaBu acted as an antioxidant in HG-induced NRK-52E cells and suppressed HG-induced apoptosis of NRK-52E cells through inhibiting HDAC2 by virtue of its anti-oxidative property.

Sodium Butyrate Inhibits Neovascularization Partially via TNXIP/VEGFR2 Pathway

“…Butyrate is one of short chain fatty acids (SCFAs) produced by intestinal bacteria in gut which ferment food fiber. As an endogenic histone deacetylase (HDAC) inhibitor, butyrate remodels the acetylating state on histone and thus gene expression profile [ 12 , 13 ]. It was also reported that butyrate increases the activity of histone acetyltransferases (HAT) and promotes the destined gene transcription [ 12 , 14 , 15 ].…”

“…In light of its profound effect on gene expression, butyrate affects various cellular events, including proliferation, cell cycle, apoptosis, differentiation, migration, and invasiveness [ 12 , 16 – 19 ]. Butyrate was confirmed to be an effective small molecule in inhibition of diabetes and various tumors [ 13 , 20 , 21 ].…”

Quantitative Reduction of Gut Microbiota-Derived Short-Chain Fatty Acids in Stool and Serum in Diabetic Kidney Disease

“…Administration of sodium butyrate (NaBu), the major members of SCFAs, ameliorates mesangial matrix expansion, brosis and in ammation in the kidneys of STZ-induced diabetic rats [30,31]. In vitro study, NaBu acted as an antioxidant in HG-induced NRK-52E cells and suppressed HG-induced apoptosis of NRK-52E cells through inhibiting HDAC2 [32]. In vivo study, dietary ber protects against DKD through modulation of the gut microbiota, enrichment of SCFA-producing bacteria, and increased SCFA production, so that it reduced expression of genes encoding in ammatory cytokines, chemokines, and brosis-promoting proteins in diabetic kidneys via GPR43 and GPR109A [33].Recent studies found GPR41 and GPR43 protein expressed in the distal renal tubules and collecting tubules, and found SCFAs lowered TNF-α induced MCP-1 expression by reducing phosphorylation of p38 and JNK in a GPR41/43-dependent manner in human renal cortical epithelial cells(HRCEs) [34].…”

Roles of Gut Microbial Metabolites in Diabetic Kidney Disease

“…SCFAs can be used by the host for the biosynthesis of lipids, cholesterol, and proteins or as an energy source by gut mucosal cells (18). The effects of SCFAs are in part mediated by G-protein coupled receptors (GPR41, GPR43, and GPR109A) and histone deacetylase (HDAC), which are related to oxidative stress, immune, and inflammatory responses (19)(20)(21)(22).…”