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Abstract: FR-PO328

Phenotypic Quantification of a NPHS1 Knockout Mouse Model

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Merz, Lea Maria, Department of Pediatrics, University Hospital Leipzig, Leipzig, Saxony, Germany
  • Buerger, Florian, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Saida, Ken, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Mertens, Nils David, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Lemberg, Katharina, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Yousef, Kirollos, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Mansour, Bshara, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Kolvenbach, Caroline Maria, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Shril, Shirlee, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Schneider, Ronen, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Department of Pediatric Nephrology, Boston Children's Hospital & Harvard Medical School, Boston, Massachusetts, United States
Background

Steroid-resistant nephrotic (SRNS) syndrome is the second most frequent cause of chronic kidney disease before the age of 25 years. Nephrin (NPHS1) is localized at the slit diaphragm of glomerular podocytes and plays a pivotal role in the filtration barrier. Biallelic mutations in NPHS1 cause congenital nephrotic syndrome type 1 (CNS-1). To date, no causative therapy for CNS-1 is available. Recently, AAV vectors targeting the glomerular podocyte, have been assessed as a means for gene replacement therapy (Rocca, Methods Mol Biol 1937:227, 2019).

Methods

We acquired a conditional transgenic mouse model (Nphs1tm1.1Pgarg/J) using a podocyte-specific Cre-recombinase (Verma, Plos One 13(6):e0198013, 2018). We phenotypically characterized the nephrin-deficient mice by analyzing the presence of proteinaceous casts by renal histology, and density of podocyte foot processes by TEM. We also performed proteinuria measurements at different time points. To quantify foot process effacement, we detected the number of foot process cross-sections per length of the glomerular basement membrane (GBM). Furthermore, we characterized median survival of the Nphs1-/- mice in comparison to wildtype or heterozygous controls, to determine potential time-points of postnatal treatment.

Results

We found the average survival rate after birth to be 17 days (range from 9-23 days, n=8). The Nphs1-/- mice develop proteinuria within the first week, increasing to massive proteinuria 3-4.1 mg albumin/g creatinine from day 9 until time of death. The average density of foot processes per GBM length was 1.5 fp/µm in the Nphs1-/- mice compared to 1.7 fp/µm in the controls at day 9. At day 14 we detected a more distinct difference with an average of 1.2 fp/µm in knockout mice and 2.3 fp/µm in the matching controls.

Conclusion

We quantitatively characterized the phenotype of the mouse model published by Verma et al. (Plos One 13(6):e0198013, 2018).

Funding

  • NIDDK Support