miR-93 regulates Msk2-mediated chromatin remodelling in diabetic nephropathy

• Published in: Nature communications Vol. 7; no. 1; pp. 12076 - 15
• Main Authors: Badal, Shawn S., Wang, Yin, Long, Jianyin, Corcoran, David L., Chang, Benny H., Truong, Luan D., Kanwar, Yashpal S., Overbeek, Paul A., Danesh, Farhad R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-06-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/77; 38/91; 631/337/100/102; 631/337/384/331; 631/80/86; 64; 64/60; 692/699/1585/2759/1419; Aged; Animals; Biology; Chromatin Assembly and Disassembly; Diabetes; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Epigenetics; Female; Glucose; Humanities and Social Sciences; Humans; Kidneys; Kinases; Male; Medicine; Metabolism; Mice, Transgenic; MicroRNAs; MicroRNAs - metabolism; Middle Aged; multidisciplinary; Pathogenesis; Phosphorylation; Podocytes - metabolism; Podocytes - ultrastructure; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Science; Science (multidisciplinary); United States > US; Texas; Chicago Illinois
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12076

How the kidney responds to the metabolic cues from the environment remains a central question in kidney research. This question is particularly relevant to the pathogenesis of diabetic nephropathy (DN) in which evidence suggests that metabolic events in podocytes regulate chromatin structure. Here, we show that miR-93 is a critical metabolic/epigenetic switch in the diabetic milieu linking the metabolic state to chromatin remodelling. Mice with inducible overexpression of a miR-93 transgene exclusively in podocytes exhibit significant improvements in key features of DN. We identify miR-93 as a regulator of nucleosomal dynamics in podocytes. miR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk2, a histone kinase, and its substrate H3S10. These findings implicate a central role for miR-93 in high glucose-induced chromatin remodelling in the kidney, and provide evidence for a previously unrecognized role for Msk2 as a target for DN therapy.
Podocyte injury is central to kidney dysfunction in diabetic nephropathy. Here the authors show that Msk2 is a target of miR-93 and this interaction mediates pathogenic chromatin remodelling in diabetic nephropathy.