MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction.

Abstract

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.

• Authors: Chun-Liang Lin, Pei-Hsien Lee, Yung-Chien Hsu, Chen-Chou Lei, Jih-Yang Ko, Pei-Chin Chuang, Yu-Ting Huang, Shao-Yu Wang, Shin-Long Wu, Yu-Shan Chen, Wen-Chih Chiang, Jochen Reiser, Feng-Sheng Wang
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 8 Pg. 1698-709 (Aug 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24578127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American Society of Nephrology.

Chemical References

• Histones
• MIRN29 microRNA, mouse
• Membrane Proteins
• MicroRNAs
• nephrin
• Histone Deacetylases

Topics

• Acetylation
• Animals
• Diabetes Mellitus, Experimental (etiology, metabolism, pathology)
• Histone Deacetylases (physiology)
• Histones (physiology)
• Hyperglycemia (etiology, metabolism, pathology)
• Male
• Membrane Proteins (metabolism)
• Mice, Transgenic
• MicroRNAs (physiology)
• Podocytes (physiology)
• Signal Transduction (physiology)