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.
Highlights
How the kidney responds to the metabolic cues from the environment remains a central question in kidney research
Pod-Cre-ERT2 mice were crossed with mTomato/membrane-targeted GFP (mGFP) reporter mice to further validate the podocyte-specific activity of our Cre mice[17]
We elucidated a signalling pathway, whereby metabolically regulated miR-93 has an important role in translating metabolic cues into chromatin reorganization in diabetic nephropathy (DN)
Summary
How the kidney responds to the metabolic cues from the environment remains a central question in kidney research This question is relevant to the pathogenesis of diabetic nephropathy (DN) in which evidence suggests that metabolic events in podocytes regulate chromatin structure. MiR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk[2], 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 Msk[2] as a target for DN therapy. Our results support a model in which miR-93 by targeting Msk[2], a chromatin modifier, regulates a group of seemingly unrelated as well as functionally related genes, greatly amplifying its downstream effect in DN
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