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Abstract: TH-PO755

The Mouse Nephrotoxic Serum (NTS) Model to Screen Novel Drugs for Reversal of Podocyte Injury

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Hinke, Simon A., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Cavanaugh, Cassandre, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Rankin, Matthew M., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Meng, Rong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • D'Aquino, Katharine, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Pissios, Pavlos, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Nawrocki, Andrea R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
Background

Kidney podocyte drug targets are being studied for treatment of diabetic kidney disease (DKD) and chronic kidney disease (CKD), requiring screening models to triage agents for efficacy testing. Nephrotoxic serum (NTS) causes nephritis driven by immune complex-mediated inflammation of the kidneys. Methods of induction vary widely: kidney immunogen used, source of serum, presence of adjuvant or pre-immunization, dose of NTS, and/or mouse strain. A new batch of commercially available NTS (Probetex, San Antonio, TX) has been validated for rats but not mice. Characterization of this mouse model will facilitate rapid screening podocyte targeting agents for DKD/CKD.

Methods

An IV dose range of new Probetex NTS was tested in four strains of mice. Female C57Bl/6 and DBA/1 mice were chosen for more testing. Kidney injury model induction was tested using single or multiple sequential daily NTS injections. Disease model severity was assessed measuring serum creatinine, BUN, urine albumin to creatinine ratio (UACR) and Luminex Kidney Injury Panels. Upon establishing mouse strain sensitivity to NTS, the effect of clinically approved standard of care agents lisinopril or losartan to preserve kidney function was assessed.

Results

One dose of new NTS did not replicate reported body weight effects in mice; small UACR effects were noted but less than published literature. In contrast, two or three daily NTS injections caused an increase serum creatinine, BUN and UACR, with sensitivity of DBA1 mice being greater than C57 mice. Comparing fold-increase in UACR to PBS control mice, two doses of NTS induced 6.8±1.7 and 149±64 fold-increases, and three doses of NTS induced 217±36 and 292±117 fold-increases, in C57 and DBA1 mice respectively. Lisinopril or losartan treatment were both able to attenuate the NTS-induced kidney injury by over 65%, as assessed by UACR changes, in either 2- or 3-dose NTS injury paradigms in DBA1 mice, with a concomitant improvement in tissue histopathology.

Conclusion

The new Probetex NTS was validated for use in mice to generate a screening model for podocyte injury. The differential sensitivity of C57 vs DBA1 mice, and the ability to alter the disease severity in each model by modifying the NTS-injection protocol will permit tailoring the degree of injury relevant to the research question.

Funding

  • Commercial Support – Janssen Pharmaceutical Companies of J&J