Elevated expression of HDAC6 in clinical peritoneal dialysis patients and its pathogenic role on peritoneal angiogenesis

Renal Failure

Yingfeng Shi¹  Yi Wang¹  Xiaoyan Ma¹  Shougang Zhuang¹  Min Tao¹  Na Liu¹  Jun Ni¹  Yan Hu¹  Xiujuan Zang²  Andong Qiu³ 

[1] Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine;Department of Nephrology, Shanghai Songjiang District Central Hospital;School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University;

关键词: histone deacetylase 6;    peritoneal fibrosis;    peritoneal dialysis;    angiogenesis;    vascular endothelial growth factor;   

DOI  :  10.1080/0886022X.2020.1811119

来源: DOAJ

【 摘 要 】

Peritoneal dialysis (PD) is an important renal replacement therapy for end-stage renal disease (ESRD) patients. However, its complications, such as peritoneal fibrosis (PF) and angiogenesis can cause ultrafiltration failure and PD termination. Histone deacetylase 6 (HDAC6) has been demonstrated to be involved in PF. However, its underlying role in peritoneal angiogenesis is still unknown and clinical value needs to be explored. In this study, we analyzed the expression of HDAC6 in the peritoneum from patients with non-PD and PD-related peritonitis and dialysis effluent from stable PD patients. Our study revealed that HDAC6 expressed highly in the peritoneum with peritonitis and co-stained with α-smooth muscle actin (α-SMA), a biomarker of the myofibroblast. And the level of HDAC6 in the dialysate increased with time and positively correlated with transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), and negatively with cancer antigen 125 (CA125). In vitro, blockading HDAC6 with a selective inhibitor tubastatin A (TA) or silencing HDAC6 with a small interfering RNA (siRNA) prominently decreased IL-6-stimulated VEGF expression in cultured human peritoneal mesothelial cells (HPMCs), and inhibited proliferation and vasoformation of human umbilical vein endothelial cells (HUVECs). TA or HDAC6 siRNA also suppressed the expression of Wnt1, β-catenin, and the phosphorylation of STAT3 in IL-6-treated HPMCs. In summary, HDAC6 inhibition protects against PD-induced angiogenesis through suppression of IL-6/STAT3 and Wnt1/β-catenin signaling pathway, subsequently reducing the VEGF production and angiogenesis. It could become a new therapeutic target or forecast biomarker for PF, inflammation, and angiogenesis in the future.

【 授权许可】

Unknown