Renal phenotype is exacerbated in Os and lpr double mutant mice

George Jarad, Sujata Lakhe-Reddy, Jeffrey Blatnik, Morgan Koepke, Shenaz Khan, M. Ashraf El-Meanawy, Andrew S. O'Connor, John A. Sedor, Jeffrey R. Schelling

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4 Scopus citations

Abstract

Background. ROP-Os/+ mice are born with oligosyndactyly and oligonephronia and develop renal dysfunction, which includes renal tubular epithelial cell (RTC) Fas-dependent apoptosis and tubular atrophy. MRL/lpr mice harbor a Fas-inactivating mutation and develop glomerulonephritis, whereas mice expressing lpr on a C3H background demonstrate no renal phenotype. We hypothesized that crossing ROP-Os/+ with CH3-lpr/lpr mice would rescue the Os/+ renal phenotype by reducing Fas-dependent RTC apoptosis. Methods. ROP-Os/+ mice were intercrossed with C3H-lpr/lpr mice and F2 generation animals were phenotyped by kidney weight, serum creatinine, and albuminuria. Kidney sections were scored for histopathology and apoptosis. Univariate and multivariate analyses were used to examine additive effects of Os and lpr on renal phenotype. Results. By 16 weeks, F2 Os/+ lpr/lpr mice developed significantly more albuminuria, glomerulosclerosis, and interstitial inflammation compared to Os/+ +/+ mice. Glomerular cell apoptosis was increased in Os/+ lpr/lpr compared to Os/+ +/+ mice, with no significant difference in RTC apoptosis. A statistically significant Os-lpr effect on renal phenotype was demonstrated by multivariate analysis, which exceeded the combined independent effects if Os and lpr, indicating a biologic interaction exists between Os and lpr. Conclusion. Os/+ mice with a superimposed lpr mutation displayed a more severe renal phenotype, rather than phenotype rescue, suggesting that Fas pathway activation is necessary to delete cells resulting from Os-dependent injury. We further propose that an Os-lpr gene interaction and/or mixed ROP-C3H genetic background regulated the renal phenotype, consistent with the concept that chronic renal disease pathogenesis reflects effects of multiple nephropathy susceptibility alleles.

Original languageEnglish
Pages (from-to)1029-1035
Number of pages7
JournalKidney International
Volume66
Issue number3
DOIs
StatePublished - Sep 2004
Externally publishedYes

Keywords

  • Albuminuria
  • Glomerulosclerosis
  • Mouse models
  • Proteinuria
  • Renal disease progression

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    Jarad, G., Lakhe-Reddy, S., Blatnik, J., Koepke, M., Khan, S., El-Meanawy, M. A., O'Connor, A. S., Sedor, J. A., & Schelling, J. R. (2004). Renal phenotype is exacerbated in Os and lpr double mutant mice. Kidney International, 66(3), 1029-1035. https://doi.org/10.1111/j.1523-1755.2004.00851.x