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

Nat Commun. 2016 Jun 28;7:12076. doi: 10.1038/ncomms12076.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Chromatin Assembly and Disassembly*
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / metabolism
  • Female
  • Humans
  • Male
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Middle Aged
  • Podocytes / metabolism
  • Podocytes / ultrastructure
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*

Substances

  • MicroRNAs
  • Mirn93 microRNA, mouse
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka4 protein, mouse