Renal phenotype is exacerbated in Os and lpr double mutant mice.
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 F(2) 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, F(2)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.


CONCLUSIONS
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.
Jarad
George
G
Division of Nephrology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Lakhe-Reddy
Sujata
S
Blatnik
Jeffrey
J
Koepke
Morgan
M
Khan
Shenaz
S
El-Meanawy
M Ashraf
MA
O'Connor
Andrew S
AS
Sedor
John R
JR
Schelling
Jeffrey R
JR
D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D005838:Genotype; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000473:pathology / Q000503:physiopathology; D008181:Lupus Nephritis / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr; D009929:Organ Size; D010641:Phenotype; D013576:Syndactyly / Q000150:complications / Q000235:genetics*; D014034:Toes / Q000002:abnormalities; D019014:fas Receptor / Q000235:genetics
D019014:fas Receptor