MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

• Published in: Journal of the American Society of Nephrology Vol. 25; no. 8; pp. 1698 - 1709
• Main Authors: Lin, Chun-Liang, Lee, Pei-Hsien, Hsu, Yung-Chien, Lei, Chen-Chou, Ko, Jih-Yang, Chuang, Pei-Chin, Huang, Yu-Ting, Wang, Shao-Yu, Wu, Shin-Long, Chen, Yu-Shan, Chiang, Wen-Chih, Reiser, Jochen, Wang, Feng-Sheng
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.08.2014
• Subjects: Acetylation; Animals; Basic Research; Biological and medical sciences; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Histone Deacetylases - physiology; Histones - physiology; Hyperglycemia - etiology; Hyperglycemia - metabolism; Hyperglycemia - pathology; Male; Medical sciences; Membrane Proteins - metabolism; Mice, Transgenic; MicroRNAs - physiology; Nephrology. Urinary tract diseases; Podocytes - physiology; Signal Transduction - physiology; Transmembrane protein; Nephrology; RNA interference; Micro RNA; Kidney; Urology; Renal glomerulus; Podocyte; Gene silencing; Hyperglycemia; Nephrin; Urinary system; Dysfunction; Acetylation
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2013050527

Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemia-induced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR-29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.