Abstract: TH-PO704

Effects of Clinically Validated Renal Therapies in the Renin AAV db/db Uninephrectomized (uNx) Mouse Model

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Harlan, Shannon Marie, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Heuer, Josef G., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Breyer, Matthew D., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Duffin, Kevin L., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Wei, Tao, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Baker, Hana, Eli Lilly and Company, Indianapolis, Indiana, United States
Background

The recently developed ReninAAV db/db uNx mouse model, exhibits key hallmarks of advanced human diabetic kidney disease (DKD), including progressive elevations in albuminuria, increased serum creatinine, loss of glomerular filtration rate and pathological changes similar to human DKD. The renal transcriptome changes in this model were demonstrated to be more similar to human DKD when compared to the db/db eNOS-/- model. Recent clinical studies have demonstrated inhibiting the JAK/STAT pathway or SGLT2 inhibition improves renal function on top of ACEi or ARB. To further explore similarities of this model to human DKD we tested the response of Renin AAV db/db uNx to clinically validated therapeutics.

Methods

Four weeks after ReninAAV, mice were randomized and treated with vehicle, lisinopril (ACEi), losartan (ARB), Canagliflozin (SGLT2i) or Ruxolotinib (JAK/STATi). At 48 hours or 2 weeks post treatment urine was collected for measurement of albumin to creatinine ratio (ACR) and serum collected for measurement of clinical parameters and kidney collected for gene expression.

Results

Vehicle treated ReninAAV mice exhibited significant (p<0.02) elevations in ACR compared to baseline at 48 hour (+53,776ug/mg) and 2 weeks (+12,842ug/mg). Lisinopril and losartan reduced ACR (p<0.01) as compared to baseline at both 48 hour (-15,973ug/mg and -17,655ug/mg respectively) and 2 week time points (-15,622ug/mg and -7,774ug/mg respectively. Treatment with Canagliflozin led to significant (p<0.01) reductions in ACR at 48 hours (-12,238ug/mg) as compared to baseline, with no reductions (p=0.5) in ACR at 2 weeks (+257ug/mg). Ruxolotinib treated mice did not exhibit a significant lowering of ACR at 48 hours, with only a trend (p=0.07) at 2 weeks post treatment (-6,569ug/mg). However, significant (p<0.01) reductions from vehicle treated mice were observed in both Canagliflozin and Ruxolotinib treated mice (-5,791ug/mg and -9,103ug/mg, respectively) indicating a halting of disease progression. Effects of the inhibitors on gene expression in the model were compared.

Conclusion

The results support further clinical validation of this mouse model of DKD and provide further insights into disease pathophysiology allowing for a better understanding of human disease progression and identification of potential new targets.

Funding

  • Commercial Support