Identifying Renal Signatures of Coxsackievirus Infection and Diabetes in Non-Obese Diabetic Mice

Presentation Number: LB MON 78
Date of Presentation: April 3rd, 2017

Debra Walter*1, Frank L Schwartz2, Karen T Coschigano2 and Kelly Dawn McCall2
1Ohio University, Athens, OH, 2Ohio University Heritage College of Osteopathic Medicine, Athens, OH


Diabetes is the leading cause of end stage renal disease (ESRD) in the United States; however, the ability to predict which diabetic patients will go on to develop ESRD is lacking. While both type 1 (T1D) and type 2 (T2D) diabetes result in kidney injury and can be induced by genetic and environmental components, patients with T1D have a higher risk of developing ESRD over their lifetime. Furthermore, the environmental component of T1D has been understudied when considering secondary consequences such as ESRD. This study evaluates kidney injury in response to genetic (autoimmune) and environmental (viral) components of T1D initiation, both alone and together, to shed light on how kidney injury develops as a result of each. We hypothesize that the initiating factors of T1D result in similar but distinguishable kidney damage “signatures” and could be used to more accurately predict patients with T1D who will go on to develop kidney injury. Non-obese diabetic (NOD) mice spontaneously develop T1D with age, which can be accelerated by coxsackievirus (CV) infection, making an ideal model to study kidney injury resulting from both autoimmune and environmental triggers. In our study, NOD mice were infected with CV at 8 weeks of age and euthanized at 3, 7, 12 and 17-weeks post infection. Urine, serum and kidneys were collected at each time point for evaluation of diabetes and kidney injury onset and progression. Mice at each time point were categorized as non-infected/non-diabetic, non-infected/diabetic (non-fasting BG>250 mg/dl), infected/non-diabetic and infected/diabetic. Real-time RT-PCR revealed that TNFα, IL-6, TLR4 and KIM-1 were differentially expressed 12-weeks post infection, dependent on their insult. Kidney weight and albumin to creatinine ratio (ACR) were significantly elevated 17-weeks post infection in non-infected/diabetic and infected/diabetic mice compared to both non-diabetic phenotypes. Also at 17-weeks post infection, the differential gene expression of TNFα, IL-6, TLR4 and KIM-1 observed at 12-weeks had resolved; however, TGFβ1, Agt and Spp1 were now differentially expressed. These (and other) data were used to develop renal gene expression signatures for the four mouse phenotypes, revealing distinguishable signatures at all four time points. These signatures demonstrate that in some instances both CV infection and diabetes are required for observation of a significant injury phenotype suggesting the mechanism of T1D initiation is important in determining the type and severity of kidney injury that develops. These results are the forefront to developing distinct kidney injury signatures for each injury type (genetic and environmental) in diabetic patients and may one day help provide better therapeutic options and predictive measures for patients with T1D.


Nothing to Disclose: DW, FLS, KTC, KDM