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 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 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 miR29a 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.

MicroRNA-155 Deficiency Promotes Nephrin Acetylation and Attenuates Renal Damage in Hyperglycemia-Induced Nephropathy

“…This study suggests that miR-155 −/− induced markedly decreased expression of desmin and significantly increased levels of nephrin, acetylated nephrin, and WT-1. This result was consistent with recent report indicating the biologic action of noncoding miR signaling on nephrin acetylation in podocyte microenvironments [17].…”

“…Nephrin has been shown to act as a protein tyrosin kinase that triggers biologic reaction in maintaining podocyte function and renal filtration capacity in various renal disorders [14][15][16]. And recent paper demonstrated that diabetes led to a reduction in the nephrin level in conjunction with nephrin deacetylation [17]. This study suggests that miR-155 −/− induced markedly decreased expression of desmin and significantly increased levels of nephrin, acetylated nephrin, and WT-1.…”

Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

“…In 2010, investigators observed that deleting a component of the histone H3 lysine 4 methyltransferase complex from podocytes resulted in progressive proteinuria (37). Since then, altered DNA methylation patterns (38) and posttranslational histone changes (38)(39)(40) in podocytes have each been shown to affect glomerular cell permselectivity. Here, we observed that either deletion of EZH2 specifically from podocytes or systemic inhibition of EZH2 activity diminished levels of the repressive H3K27me3 mark, provoked Notch pathway activation, and sensitized mice to glomerular disease.…”

New insights on microRNAs in diabetic nephropathy: potential biomarkers for diagnosis and therapeutic targets

“…и соавт. [36] продемонстриро-вали, что гипергликемия нарушает экспрессию miR-29b в подоцитах, приводя к снижению экспрессии в них нефрина, в то время как гиперэкспрессия miR-29а в мо-дели СД у мышей позволяла эффективно поддерживать уровни нефрина и жизнеспособность подоцитов, сохра-нять функцию почек. Недавно Kanasaki K. и соавт.…”