MicroRNA-29a Promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction
Journal
Journal of the American Society of Nephrology
Journal Volume
25
Journal Issue
8
Pages
1698-1709
Date Issued
2014
Author(s)
Lin C.-L.
Lee P.-H.
Hsu Y.-C.
Lei C.-C.
Ko J.-Y.
Chuang P.-C.
Huang Y.-T.
Wang S.-Y.
Wu S.-L.
Chen Y.-S.
Reiser J.
Wang F.-S.
Abstract
Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemiainduced 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 nondiabeticmice. In vitro, interruption ofHDAC4 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, reducesmiR-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. Copyright ? 2014 by the American Society of Nephrology.
SDGs
Other Subjects
antisense oligonucleotide; glucose; histone deacetylase 4; histone H3; microRNA 29a; nephrin; histone; histone deacetylase; membrane protein; microRNA; MIRN29 microRNA, mouse; nephrin; animal cell; animal experiment; animal model; apoptosis; Article; cell culture; cell viability; controlled study; deacetylation; disease association; enrichment culture; gene silencing; glomerulus; histone ubiquitination; homeostasis; hyperglycemia; in vitro study; inflammation; kidney dysfunction; kidney function; mouse; nonhuman; podocyte; priority journal; protein acetylation; protein degradation; protein expression; protein function; proteinuria; regulatory mechanism; renal protection; signal transduction; streptozotocin-induced diabetes mellitus; urinary excretion; acetylation; animal; Diabetes Mellitus, Experimental; hyperglycemia; male; metabolism; pathology; physiology; transgenic mouse; Acetylation; Animals; Diabetes Mellitus, Experimental; Histone Deacetylases; Histones; Hyperglycemia; Male; Membrane Proteins; Mice, Transgenic; MicroRNAs; Podocytes; Signal Transduction
Publisher
American Society of Nephrology
Type
journal article