467-P: Brown Fat Original Mir-30b Targeting Renal RUNX1 to Improve Diabetic Nephropathy

Abstract

It has been verified that adipose tissue was the major source of circulating microRNAs (miRNA), which could target downstream genes in distant organs such as liver. Here we show that brown adipose tissue (BAT) transplantation from healthy mice donor could reactivate endogenous BAT activity of diabetic mice induced by high fat diet (HFD) and streptozotocin (STZ) injection. BAT activation increased circulating miR-30b level and significantly improved diabetic nephropathy. In vitro, miR-30b was significantly downregulated by TGF β1 in HK-2 cells. In vivo, agomiR-30b was directly administered to the BAT of diabetic mice (0.25nmol/g body weight) twice per week for 4 consecutive weeks. Over-expressing miR-30b markedly decreased fibronectin expression, coupled with downregulated Runt-related transcription factor 1(Runx1) and snail family zinc finger 1 (Snail1) in the kidney of diabetic mice, while silencing of miR-30b displayed the opposite features. Next, knockdown or overpression of Runx1 both in vitro by using siRUNX1 or pCMV-RUNX1, and in vivo by AAV-U6-shRunx1 or AAV-EF1a-Runx1 respectively, could mimic the above phenotype of miR-30b mimic and inhibitor treatment respectively. Moreover, Runx1 promoted TGFβ1-induced fibrosis through upregulating PI3K pathway. These results suggest that BAT transplantation ameliorates diabetic nephropathy in mice through reactivating endogenous BAT and increasing circulating miR-30b level, which subsequently target renal Runx1 and Snail1, to improve renal fibrosis. BAT-original miRNAs might be a promising target for kidney protection in diabetes mellitus. Disclosure M. Guan: None. Funding National Natural Science Foundation of China (81870612, 81628004, 31400992, 81470047); Guangdong Science and Technology Project (2019A1515011997)