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MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction.
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.
Afiliação
  • Lin CL; Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; School of Traditional Chinese Medicine and.
  • Lee PH; Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan;
  • Hsu YC; Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan;
  • Lei CC; Department of Nephrology and Kidney and Diabetic Complications Research Team, Chang Gung Memorial Hospital, Chiayi, Taiwan;
  • Ko JY; Departments of Orthopedic Surgery and Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;
  • Chuang PC; Departments of Orthopedic Surgery and.
  • Huang YT; Department of Nephrology and.
  • Wang SY; Department of Nephrology and.
  • Wu SL; Departments of Orthopedic Surgery and.
  • Chen YS; Departments of Orthopedic Surgery and.
  • Chiang WC; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
  • Reiser J; Department of Medicine, Rush University Medical Center, Chicago, Illinois; and.
  • Wang FS; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Medical Research and Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, TaoYuan, Taiwan wangfs@ms33.hinet.net.
J Am Soc Nephrol ; 25(8): 1698-709, 2014 Aug.
Article em En | MEDLINE | ID: mdl-24578127
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: MicroRNAs / Diabetes Mellitus Experimental / Podócitos / Hiperglicemia / Proteínas de Membrana Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: MicroRNAs / Diabetes Mellitus Experimental / Podócitos / Hiperglicemia / Proteínas de Membrana Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article