Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1) in diabetic nephropathy

• Published in: PloS one 2011-04, Vol.6 (4), p.e18671
• Main Authors: Alvarez, M Lucrecia, DiStefano, Johanna K
• Format: Article
• Language: English
• Subjects: Analysis; Biology; Chronic kidney failure; Collagen (type IV); Development and progression; Diabetes mellitus; Diabetic nephropathies; Diabetic Nephropathies - genetics; Diabetic nephropathy; End-stage renal disease; Enzyme-linked immunosorbent assay; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fibronectin; Fibronectins; Gene expression; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Genes; Genomics; Glucose; Glucose - pharmacology; Humans; Kidney diseases; Kidney transplantation; Kinases; Lymphomas; Medicine; Mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; Mesangial Cells - pathology; Messenger RNA; Models, Biological; Molecular modelling; mRNA; Nephropathy; Plasmacytoma; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitors; Polyamide-imides; Proteins; Proteins - genetics; Proteins - metabolism; Regulators; Ribonucleic acid; RNA; RNA, Long Noncoding; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-mediated interference; Rodents; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-a; Transforming growth factor-b1; Translocation; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018671

We previously observed association between variants in the plasmacytoma variant translocation 1 gene (PVT1) and end-stage renal disease (ESRD) attributed to both type 1 and type 2 diabetes, and demonstrated PVT1 expression in a variety of renal cell types. While these findings suggest a role for PVT1 in the development of ESRD, potential mechanisms for involvement remain unknown. The goal of this study was to identify possible molecular mechanisms by which PVT1 may contribute to the development and progression of diabetic kidney disease. We knocked-down PVT1 expression in mesangial cells using RNA interference, and analyzed RNA and protein levels of fibronectin 1 (FN1), collagen, type IV, alpha 1 (COL4A1), transforming growth factor beta 1 (TGFB1) and plasminogen activator inhibitor-1 (SERPINE1 or PAI-1) by qPCR and ELISA, respectively. PVT1 expression was significantly upregulated by glucose treatment in human mesangial cells, as were levels of FN1, COL4A1, TGFB1, and PAI-1. Importantly, PVT1 knockdown significantly reduced mRNA and protein levels of the major ECM proteins, FN1 and COL4A1, and two key regulators of ECM proteins, TGFB1 and PAI-1. However, we observed a higher and more rapid reduction in levels of secreted FN1, COL4A1, and PAI-1 compared with TGFB1, suggesting that at least some of the PVT1 effects on ECM proteins may be independent of this cytokine. These results indicate that PVT1 may mediate the development and progression of diabetic nephropathy through mechanisms involving ECM accumulation.