miR-299a-5p is a mediator of fibrosis in diabetic kidney disease by regulating follistatin and cripto-1

Glomerular extracellular matrix protein accumulation, mediated largely by mesangial cells(MC), is a defining feature of diabetic kidney disease(DKD). Previously we showed that TGFβ1, a profibrotic cytokine in kidney fibrosis, inhibits expression of the antifibrotic follistatin through induction of microRNA-299a-5p. Whether this microRNA contributes to DKD is unknown. We show that microRNA-299a-5p is increased in mouse and human diabetic kidneys, and by high glucose in primary MC. Overexpression of microRNA-299a-5p in MC increased basal ECM 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. Induction of microRNA-299a-5p by high glucose mediated the MC fibrotic response by inhibiting follistatin and cripto-1 which led to increased activin A and TGFβ1 signaling. In vivo, microRNA-299a-5p inhibition reduced clinical markers of DKD, and was associated with increased expression of follistatin and cripto-1. Thus, microRNA-299a-5p is an important mediator of glucose-induced profibrotic responses in diabetic kidneys.