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Abstract: FR-PO330

FVB/N-Nos1apEx3-/Ex3- Mice Develop Severe Glomerular Kidney Disease, Which Is Ameliorated by Antiproteinuric Treatment

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Buerger, Florian, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Liang, Lorrin, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Salmanullah, Daanya, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Sharma, Vineeta, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ball, David A., Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Nephrotic syndrome (NS) is a leading cause of pediatric chronic kidney disease and frequently caused by Mendelian genetic variants. We previously discovered recessive NOS1AP variants as a novel cause of early onset NS in children and observed moderate glomerular disease without kidney failure in Nos1apEx3-/Ex3- mice on a C57BL/6 background (Majmundar & Buerger Sci. Adv. 7:1386, 2021). We, next, hypothesized that the Nos1apEx3-/Ex3- phenotype depends on the genetic background and that FVB/N and 129/sv mice may fully recapitulate the human disease.

Methods

C57BL/6-Nos1apEx3-/Ex3- mice were crossed onto FVB/N and 129/sv backgrounds. Urine albumin-to-creatinine ratios (ACR) in urine, blood parameters of kidney failure, and histology by light microscopy were measured.

Results

FVB/N-Nos1apEx3-/Ex3- mice developed significantly increased albuminuria, beginning at weaning age, relative to wildtype or heterozygote controls. ACRs in FVB/N-Nos1apEx3-/Ex3- mice were one order of magnitude higher than in C57BL/6-Nos1apEx3-/Ex3- and 129/sv mice-Nos1apEx3-/Ex3- at 3-6 months (mean ACRs 13.47-16.04 g/g, 0.86-1.53 g/g, and 0.99-1.69 g/g, respectively). Furthermore, FVB/N-Nos1apEx3-/Ex3- mice exhibited markedly reduced serum albumin, elevated serum levels of renal dysfunction marker BUN, and increased mortality compared to controls, which were all previously not observed on the C57BL/6 background. Histologic studies demonstrated increased mesangial matrix deposition, proteinaceous tubular casts, and tubular dilation in homozygous FVB/N mouse kidneys. FVB/N-Nos1apEx3-/Ex3- mice with comparable baseline ACRs received drinking water with vehicle (water), 100 mg/L lisinopril, or 200 mg/L lisinopril at 6 weeks of age. Lisinopril treatment resulted in reduced albuminuria (mean ACRs between 2-12 weeks of treatment: vehicle, 14.06-29.84 g/g; 100 mg/L lisinopril, 5.54-9.97 g/g; 200 mg/L lisinopril, 7.15-11.20 g/g). Finally, lisinopril-treated mice exhibited increased survival at 14 weeks of treatment (11/11 viable) relative to vehicle-treated FVB/N-Nos1apEx3-/Ex3- mice (1/5 viable).

Conclusion

FVB/N-Nos1apEx3-/Ex3- mice develop severe proteinuric kidney disease, consistent with human SRNS, which is ameliorated by ACE inhibition.

Funding

  • NIDDK Support