A microRNA circuit mediates transforming growth factor-?1 autoregulation in renal glomerular mesangial cells.

ABSTRACT: Enhanced transforming growth factor-?1 (TGF-?1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-?1 promoter is positively controlled by the E-box regulators, upstream stimulatory factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-?1 is autoregulated by itself. As changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-?1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-?1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-?1 promoter was upregulated by TGF-?1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-?1 expression. TGF-?1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-?1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1, and TGF-?1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-?1 signaling, accelerating chronic fibrotic diseases such as diabetic nephropathy.

SUBMITTER: Kato M 

PROVIDER: S-EPMC3337779 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature