Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy

被引：213

作者：

Wang, Xiaojie ^{[1
]}

Liu, Jiang ^{[1
]}

Zhen, Junhui ^{[2
]}

Zhang, Chun ^{[3
]}

Wan, Qiang ^{[4
]}

Liu, Guangyi ^{[5
]}

Wei, Xinbing ^{[1
]}

Zhang, Yan ^{[1
]}

Wang, Ziying ^{[1
]}

Han, Huirong ^{[1
]}

Xu, Huiyan ^{[1
]}

Bao, Chanchan ^{[6
]}

Song, Zhenyu ^{[1
]}

Zhang, Xiumei ^{[1
]}

Li, Ningjun ^{[7
]}

Yi, Fan ^{[1
]}

机构：

[1] Shandong Univ, Sch Med, Dept Pharmacol, 44 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China

[2] Shandong Univ, Sch Med, Dept Pathol, Jinan 250012, Shandong, Peoples R China

[3] Huazhong Univ Sci & Technol, Ton gji Med Coll, Union Hosp, Dept Nephrol, Wuhan 430074, Peoples R China

[4] Shandong Univ, Prov Hosp, Dept Nephrol, Jinan 250012, Shandong, Peoples R China

[5] Shandong Univ, Qilu Hosp, Dept Nephrol, Jinan 250012, Shandong, Peoples R China

[6] Shandong Univ, Microscopy Characterizat Platform, Jinan 250012, Shandong, Peoples R China

[7] Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA

来源：

KIDNEY INTERNATIONAL | 2014年 / 86卷 / 04期

关键词：

autophagy; diabetic complications; gene therapy; histone deacetylases; podocyte; RENAL INJURY; AUTOPHAGY; ACETYLATION; INHIBITION; GLOMERULOSCLEROSIS; DEFICIENCY; EXPRESSION; RESISTANCE; PROTECTS; ALPHA;

D O I：

10.1038/ki.2014.111

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-beta (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.

引用

页码：712 / 725

页数：14

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