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

The University of Chicago, Section of Nephrology, Department of Medicine, Chicago, Illinois, USA

¹Correspondence: Section of Nephrology, The University of Chicago, 5841 South Maryland Ave., MC5100, AMB-S523, Chicago, IL 60637, USA. E-mail: rquigg{at}uchicago.edu

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.

Key Words: diabetes • microRNA • glomerulus • extracellular matrix

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