Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy.
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-β (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.
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Xiaojie
X
Wang
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Jiang
J
Liu
Department of Pathology, Shandong University School of Medicine, Jinan, China.
Junhui
J
Zhen
Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chun
C
Zhang
Department of Nephrology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
Qiang
Q
Wan
Department of Nephrology, Qilu Hospital, Shandong University, Jinan, China.
Guangyi
G
Liu
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Xinbing
X
Wei
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Yan
Y
Zhang
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Ziying
Z
Wang
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Huirong
H
Han
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Huiyan
H
Xu
The Microscopy Characterization Platform, Shandong University, Jinan, China.
Chanchan
C
Bao
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Zhenyu
Z
Song
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Xiumei
X
Zhang
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA.
Ningjun
N
Li
Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
Fan
F
Yi
D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D050199:Podocytes / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D016212:Transforming Growth Factor beta; C533423:HDAC2 protein, human; C400300:HDAC4 protein, human; C559944:HDAC4 protein, rat; C533424:Hdac2 protein, mouse; C533426:Hdac2 protein, rat; C498618:Hdac5 protein, mouse; C498619:Hdac5 protein, rat; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D005947:Glucose