Abstract
Histone deacetylase 5 (HDAC5) belongs to class II HDAC subfamily and is reported to be increased in the kidneys of diabetic patients and animals. However, little is known about its function and the exact mechanism in diabetic kidney disease (DKD). Here, we found that HDAC5 was located in renal glomeruli and tubular cells, and significantly upregulated in diabetic mice and UUO mice, especially in renal tubular cells and interstitium. Knockdown of HDAC5 ameliorated high glucose-induced epithelial–mesenchymal transition (EMT) of HK2 cells, indicated in the increased E-cadherin and decreased α-SMA, via the downregulation of TGF-β1. Furthermore, HDAC5 expression was regulated by PI3K/Akt signaling pathway and inhibition of PI3K/Akt pathway by LY294002 treatment or Akt phosphorylation mutation reduced HDAC5 and TGF-β1 expression in vitro high glucose-cultured HK2 cells. Again, high glucose stimulation downregulated total m6A RNA methylation level of HK2 cells. Then, m6A demethylase inhibitor MA2 treatment decreased Akt phosphorylation, HDAC5, and TGF-β1 expression in high glucose-cultured HK2 cells. In addition, m6A modification-associated methylase METTL3 and METTL14 were decreased by high glucose at the levels of mRNA and protein. METTL14 not METTL3 overexpression led to PI3K/Akt pathway inactivation in high glucose-treated HK2 cells by enhancing PTEN, followed by HDAC5 and TGF-β1 expression downregulation. Finally, in vivo HDACs inhibitor TSA treatment alleviated extracellular matrix accumulation in kidneys of diabetic mice, accompanied with HDAC5, TGF-β1, and α-SMA expression downregulation. These above data suggest that METTL14-regulated PI3K/Akt signaling pathway via PTEN affected HDAC5-mediated EMT of renal tubular cells in diabetic kidney disease.
Highlights
Diabetic kidney disease (DKD) is a kind of severe chronic complication of diabetes mellitus (DM) and has been reported to have multiple morphologic changes including hypertrophy and proliferation of mesangial cells, epithelial–mesenchymal transition (EMT) of renal tubular cells, apoptosis of podocytes, and so on[1]
We first revealed that Histone deacetylase 5 (HDAC5) expression was increased in renal tubular cells of diabetic mice, fibrosis region of unilateral ureteral obstruction (UUO) mice, and in vitro high glucose-cultured human renal tubular cell line (HK2)
We explored the effect of high glucose known as the main feature of diabetes mellitus on HDAC5 expression in vitro-cultured human renal tubular cells (HK2 cells) and the results showed that HDAC5 was increased by 41.01% in HK2 cells treated with high glucose (40 mmol/L glucose) for 48 h compared to those treated with normal glucose (10 mmol/L glucose) (Fig. 1C)
Summary
Diabetic kidney disease (DKD) is a kind of severe chronic complication of diabetes mellitus (DM) and has been reported to have multiple morphologic changes including hypertrophy and proliferation of mesangial cells, epithelial–mesenchymal transition (EMT) of renal tubular cells, apoptosis of podocytes, and so on[1]. TGF-β1 pathway has been demonstrated to be the important pro-fibrosis factor in the pathogenesis of diabetic kidney disease[3]. Accumulating evidence suggests that inhibition of histone deacetylase (HDAC) ameliorates diabetic kidney disease manifestations and phenotypes such as fibrosis, inflammation, cell death, and albuminuria[4,5]. HDAC inhibitor trichostatin A (TSA) was reported to suppress EMT, indicated in upregulation of E-cadherin and downregulation of collagen type I, in TGF-β1-treated human renal proximal tubular epithelial cells[6]. HDAC5 belongs to HDAC family that is found to regulate gene
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
