A susceptibility gene for kidney disease in an obese mouse model of type II diabetes maps to chromosome 8

Streamson Chua, Yifu Li, Shun Mei Liu, Ruijie Liu, Ka Tak Chan, Jeremiah Martino, Zongyu Zheng, Katalin Susztak, Vivette D. D'Agati, Ali G. Gharavi

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)453-462
Number of pages10
JournalKidney international
Volume78
Issue number5
DOIs
Publication statusPublished - Sep 2010

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Keywords

  • diabetic glomerulopathy
  • diabetic nephropathy
  • genetic renal disease

ASJC Scopus subject areas

  • Nephrology

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