Plasmacytoma Variant Translocation 1 (PVT1) Gene as a Potential Novel Target for the Treatment of Diabetic Nephropathy

RESEARCH IN CONTEXT: What is already known about this subject: The noncoding gene PVT1 was highly expressed in mice and patients with DN; PVT1 promotes DN through increasing extracellular matrix (ECM) accumulation in vitro; Silencing of PVT1 attenuated secretion of ECM proteins and delayed podocyte apoptosis in vitro. What is the key question: Does the inhibition of the noncoding gene PVT1 in a diabetic nephropathy mouse model either prevent or delay the onset of diabetic nephropathy? What are the new findings: Silencing of PVT1 ameliorates DN in terms of kidney function in a diabetic nephropathy mouse model independent of blood glucose change; The mechanism involves downregulating TGF-β1 and PAI-1 while preserving BMP7; PVT1 plays an important role in ECM accumulation and is a potential target for the treatment of DN. How might this impact clinical practice in the foreseeable future: The present study demonstrates the application of RNAi-based therapy to delay DN progression in a murine DN model. RNAi-based therapeutics are emerging treatment strategies in cancers, infectious diseases and single gene disorders. There has already been a clinical trial using siRNA for acute kidney injury, resulting in favorable safety data. Our study provided a foundation for a possible clinical long-term RNAi-based prevention/treatment of DN. ABSTRACT: Introduction: Diabetic nephropathy (DN), a severe microvascular complication in patients with diabetes, is clinically characterized by progressive decline in glomerular filtration rate (GFR). DN is the most common cause of end-stage renal disease (ESRD), and has a consistently high mortality rate. Despite the fact that the prevalence of DN is increasing worldwide, the molecular mechanism underlying the pathogenesis of DN is not fully understood. Previous studies indicated PVT1 as a key determinant of ESRD as well as a mediator of extracellular matrix (ECM) accumulation in vitro. More investigations into the role of PVT1 in DN development are needed. Objectives: To study the effect of PVT1 silencing on progression of DN in diabetic male C57BL/6 mice at early, intermediate and relatively advanced ages. Methods: Diabetic mice were treated with either scramble-siRNA (DM + siRNA (scramble)) or PVT1-siRNA (DM + siRNA (PVT1)), whereas the control mice were normal mice without siRNA injection (Control). Blood, urine and kidney were collected at the age of 9 (young), 16 (middle-aged) or 24 (old) weeks old. Kidney function, histology and molecular gene expression were evaluated. Results: Our findings showed that silencing of PVT1 reduced kidney hypertrophy, proteinuria (UAE, UACR, UPE, UPCR), serum creatinine, serum TGF-β1, serum insulin decline, glomerular and mesangial areas, and increased creatinine clearance in diabetic mice to levels closer to the age-matched controls. Also, silencing of PVT1 markedly suppressed the upregulation of PAI-1, TGF-β1, FN1, COL4A1, and downregulation of BMP7. Conclusion: Silencing of PVT1 ameliorates DN in terms of kidney function and histology in diabetic mice. The renoprotection is attributed to the reduction in ECM accumulation, TGF-β1 elevation and insulin decline. PVT1 is suggested to play an important role in ECM accumulation which makes it a possible target for the treatment of DN.