A susceptibility gene for kidney disease in an obese mouse model of type II
diabetes maps to chromosome 8.
Authors Chua S, Li Y, Liu SM, Liu R, Chan KT, Martino J, Zheng Z, Susztak K, D'Agati VD,
Gharavi AG
Submitted By Erwin Bottinger on 6/10/2010
Status Published
Journal Kidney international
Year 2010
Date Published 9/1/2010
Volume : Pages Not Specified : Not Specified
PubMed Reference 20520596
Abstract Most mouse models of diabetes do not fully reproduce features of human diabetic
nephropathy, limiting their utility in inferring mechanisms of human disease.
Here we performed detailed phenotypic and genetic characterization of
leptin-receptor (Lepr) deficient mice on the FVB/NJ background (FVB(db/db)), an
obese model of type II diabetes, to determine their suitability to model human
diabetic nephropathy. These mice have sustained hyperglycemia, significant
albuminuria and characteristic diabetic renal findings including mesangial
sclerosis and nodular glomerulosclerosis after 6 months of age. In contrast,
equally obese, hyperglycemic Lepr/Sur1 deficient C57BL/6J (Sur1 has defective
insulin secretion) mice have minimal evidence of nephropathy. A genome-wide scan
in 165 Lepr deficient backcross progeny derived from FVB/NJ and C57BL/6J
identified a major locus influencing nephropathy and albuminuria on chromosome
8B1-C5 (Dbnph1 locus, peak lod score 5.0). This locus was distinct from those
contrasting susceptibility to beta cell hypertrophy and HIV-nephropathy between
the same parental strains, indicating specificity to diabetic kidney disease.
Genome-wide expression profiling showed that high and low risk Dbnph1 genotypes
were associated with significant enrichment for oxidative phosphorylation and
lipid clearance, respectively; molecular pathways shared with human diabetic
nephropathy. Hence, we found that the FVB(db/db) mouse recapitulates many
clinical, histopathological and molecular features of human diabetic
nephropathy. Identifying underlying susceptibility gene(s) and downstream
dysregulated pathways in these mice may provide insight into the disease
pathogenesis in humans.Kidney International advance online publication, 2 June
2010; doi:10.1038/ki.2010.160.

Investigators with authorship
Erwin BottingerMount Sinai School of Medicine


Abcc8ATP-binding cassette, sub-family C (CFTR/MRP), member 8