miR-299a-5p is a novel mediator of fibrosis in diabetic kidney disease through its regulation of antifibrotic proteins follistatin and cripto-1

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Abstract
Glomerular extracellular matrix protein accumulation, mediated largely by mesangial cells, is a defining feature of early diabetic kidney disease. Previously we showed that TGFβ1, a profibrotic cytokine with a well-defined pathogenic role in kidney fibrosis, inhibits expression of the antifibrotic follistatin through induction of microRNA-299a-5p. Whether this microRNA contributes to diabetic kidney disease is unknown. We show that microRNA-299a-5p is increased in mouse and human diabetic kidneys, and by high glucose in primary mesangial cells. Overexpression of microRNA-299a-5p in mesangial cells increased basal extracellular matrix protein production. Conversely, microRNA-299a-5p inhibition prevented the glucose-induced profibrotic response. Bioinformatics screening revealed that cripto-1 is also a target of microRNA-299a-5p. It is known that follistatin and cripto-1 inhibit activin A and TGFβ1 respectively. Induction of microRNA-299a-5p by high glucose mediated the mesangial cell fibrotic response by inhibiting expression of both follistatin and cripto-1 which led to increased activin A and TGFβ1 signaling. In vivo , microRNA-299a-5p inhibition reduced albuminuria, glomerular hypertrophy, loss of podocyte nephrin and extracellular matrix production, and this was associated with increased expression of follistatin and cripto-1. Thus, microRNA-299a-5p is an important mediator of glucose-induced profibrotic responses in mesangial cells and diabetic kidneys. Its inhibition may be a potential novel therapy.

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