MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy.
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-beta 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
Qiang
Q
Section of Nephrology, Department of Medicine, The University of Chicago, 5841 South Maryland Ave., MC5100, AMB-S523, Chicago, IL 60637, USA.
Wang
Youli
Y
Minto
Andrew W
AW
Wang
Jinhua
J
Shi
Qun
Q
Li
Xinmin
X
Quigg
Richard J
RJ
D000818:Animals; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis; D000071636:Protein Phosphatase 2C; D013482:Superoxide Dismutase / Q000096:biosynthesis; D015854:Up-Regulation; D054462:p21-Activated Kinases / Q000096:biosynthesis; D000099156:Superoxide Dismutase 2
D005353:Fibronectins; D035683:MicroRNAs; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D013482:Superoxide Dismutase; D054462:p21-Activated Kinases; D000099156:Superoxide Dismutase 2; C534063:MIRN377 microRNA, human; C534064:Mirn377 microRNA, mouse