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Kidney Week

Abstract: PO0647

Beneficial Effects of Tumor Necrosis Factor α Blockade in a Mouse Model of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Takahiro, Yamaji, Duke-NUS Medical School, Singapore, Singapore
  • Azushima, Kengo, Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardiorenal Medicine, Yokohama, Kanagawa, Japan
  • Gurley, Susan B., Oregon Health & Science University School of Medicine, Portland, Oregon, United States
  • Coffman, Thomas M., Duke-NUS Medical School, Singapore, Singapore

Recent studies indicate that immune activation may play a role in pathogenesis of diabetic nephropathy (DN). We have previously described a mouse model exhibiting characteristics of human DN including high-grade albuminuria and glomerulosclerosis. In this model, glomerular immune and inflammatory pathways, including networks associated with tumor necrosis factor (TNF)-α signaling are upregulated. In this study, we examine the functional impact of the TNF-α pathway in DN.


We used a mouse model combining the Akita Ins2 mutation, which causes profound type I diabetes, with a renin transgene (ReninTg) producing low level activation of the RAS. Akita-ReninTg mice on a susceptible 129 strain background exhibit cardinal features of human DN. To examine the role of TNF-α, 16-week old 129 Akita-ReninTg mice were injected with 1mg/kg/week etanercept (E) or saline vehicle (V) subcutaneously for 4 weeks while urinary albumin excretion and other parameters were monitored.


At baseline, 16-week old Akita-ReninTg mice have substantial albuminuria (1850±207 µg/day), with no significant difference between E and V groups. Levels of albuminuria increased in the V group to 3626±1024 µg/day at 20 weeks. By contrast, etanercept treatment prevented this increase in albuminuria at 20 weeks (1448±236 µg/day; p<0.01 vs V). The extent of kidney hypertrophy was also attenuated with E. Blood glucose levels were similar in E and V groups throughout the treatment period. Renal levels of NF-κB, a key mediator activated by TNF-α was significantly reduced after etanercept consistent with effective pharmacological TNF-a blockade. In addition, renal expression of KIM-1 and TGF-β were both significantly suppressed by E, consistent with reduced kidney injury and pro-fibrotic state, respectively.


In a model of DN, TNF-α blockade administered to mice with established macro-albuminuria substantially suppressed the progression of proteinuria. Etanercept also protected against kidney injury and diminished pro-fibrotic signaling. Our findings support a causal role for TNF-a in the pathogenesis of DN and indicate potential utility of TNF-α blockade in the treatment of DN.