MicroRNA‐377 is up‐regulated and can lead to increased fibronectin production in diabetic nephropathy

Abstract

Intrinsic glomerular cells in a diabetic milieu have transcriptional activation of genes that influence the development of diabetic nephropathy. The cellular repertoire of microRNAs can regulate translation of these expressed genes into proteins. Fibronectin is a key matrix protein accumulated in excess in diabetic nephropathy. Here, we exposed cultured human and mouse mesangial cells to high glucose and transforming growth factor‐β to simulate the diabetic milieu. In these conditions in vitro , as well as in mouse diabetic nephropathy models in vivo , microRNA‐377 was consistently up‐regulated relative to controls. Through a combination of computational and biological approaches, we identified relevant miR‐377 target genes. Although fibronectin was induced by miR‐377, it was not a direct target of miR‐377. However, miR‐377 led to reduced expressions of p21‐activated kinase and superoxide dismutase, which enhanced fibronectin protein production. Thus, overexpression of miR‐377 in diabetic nephropathy indirectly leads to increased fibronectin protein production;as such, miR‐377 can have a critical role in the pathophysiology of this prevalent human disease.— Wang, Q., Wang, Y., Minto, A. W., Wang, J., Shi, Q., Li, X., Quigg, R. J. MicroRNA‐377 is up‐regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 22, 4126–4135 (2008)