Plasmacytoma Variant Translocation 1 Gene (PVT1) as a Potential Novel Target for the Treatment of Diabetic Nephropathy
Mok, Sao Keng
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Diabetic nephropathy (DN) is clinically characterized by the development of proteinuria with a subsequent decline in glomerular filtration rate which progresses over time. It is a common complication in patients with diabetes, predominantly type 2 diabetes. It is the leading cause of end-stage renal disease (ESRD) and accounts for most of the reduced life expectancy in diabetic patients. Despite the prevalence of DN is increasing worldwide, the molecular mechanism underlying the pathogenesis of DN remains poorly understood. Recent genome-wide association studies suggested plasmacytoma variant translocation 1 (PVT1) is a key determinant of ESRD. Some in vitro studies suggested PVT1 plays an important role in mediating the development of DN through the extracellular matrix (ECM) accumulation. In this study, we hypothesized that PVT1 promotes the development of DN in vivo, whereas inhibition of PVT1 prevents such development through reducing ECM accumulation. To begin with, a murine model of DN was successfully established using a combination treatment of high fat diet and low dose streptozotocin in male C57BL/6 mice. This diabetic model exhibited hallmarks of DN (including hyperglycemia, kidney hypertrophy, albuminuria, reduced creatinine clearance, and increased glomerular and mesangial areas) which were not observed in the normal controls. These manifestations were significantly different from that in the age-matched normal controls (9-wk-old as young, 16-wk-old as middle-aged and 24-wk-old as old) and were intensified as the diabetic mice aged. This set of diabetic and control models were considered suitable for testing the treatment of DN. To study the role of PVT1 on progression of DN, the gene expression of PVT1 and ECM components (FN1 and COL4A1) and regulators (TGF-β1, PAI-1 and BMP7) were determined. Our results showed that the glomerular PVT1expression was significantly increased in diabetic mice when compared with the agematched controls (without disease). The upregulation of PVT1 was paralleled with upregulation of TGF-β1, PAI-1, FN1, COL4A1, while downregulation of BMP7 in diabetic model. This suggested PVT1 might play a role in ECM accumulation. We then conducted a PVT1 inhibition experiment using RNA interference. Diabetic mice were treated with either PVT1-siRNA or scramble-siRNA, and normal controls without siRNA treatment were used and compared. PVT1 expression was inhibited in diabetic mice treated with PVT1-siRNA but not in those with scramble-siRNA at all ages (young, middle-aged and old). Significant differences in blood glucose, proteinuria (UAE, UACR, UPE, UPCR), serum creatinine, creatinine clearance and glomerular mesangial areas were observed between diabetic mice with scramble-siRNA and the age-matched controls. While hyperglycemia persisted, PVT1-siRNA treatment reduced kidney hypertrophy, proteinuria (UAE, UACR, UPE, UPCR), serum creatinine, glomerular and mesangial areas, and increased creatinine clearance in diabetic mice to levels closer to the agematched controls. The PVT1-siRNA treatment markedly supressed the upregulation of TGF-β1, PAI-1, FN1, COL4A1, and downregulation of BMP7 in the diabetic mice. In conclusion, PVT1 inhibition ameliorates DN in terms of kidney function and histology in a diabetic mouse model without altering hyperglycemia. The renal protection might be resulted from the reduction of ECM accumulation through suppression of TGF-β1 and PAI-1 expression as well as the preservation of BMP7 expression. It is therefore suggested that PVT1 plays an important role in ECM accumulation and its inhibition might be a potential approach for the management of DN.