Department of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Kidney Int. 2010 Sep;78(5):453-62. doi: 10.1038/ki.2010.160. Epub 2010 Jun 2.
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.
大多数糖尿病的小鼠模型不能完全重现人类糖尿病肾病的特征，限制了它们在推断人类疾病机制方面的应用。在这里，我们对 FVB/NJ 背景下（FVB(db/db)）的瘦素受体（Lepr）缺失小鼠进行了详细的表型和遗传特征分析，这是一种 2 型糖尿病肥胖模型，以确定它们是否适合模拟人类糖尿病肾病。这些小鼠在 6 个月大后出现持续的高血糖、显著的白蛋白尿和典型的糖尿病肾脏病变，包括系膜硬化和结节性肾小球硬化。相比之下，同样肥胖、高血糖的 Lepr/Sur1 缺失 C57BL/6J（Sur1 胰岛素分泌缺陷）小鼠几乎没有肾病的证据。在源自 FVB/NJ 和 C57BL/6J 的 165 只 Lepr 缺失近交系后代中进行全基因组扫描，发现了一个主要的遗传位点，该位点影响着 8B1-C5 染色体上的肾病和白蛋白尿（Dbnph1 位点，峰值 lod 评分 5.0）。这个位点与相同亲本株系对胰岛细胞肥大和 HIV 肾病易感性的差异无关，表明它对糖尿病肾病具有特异性。全基因组表达谱分析表明，高风险和低风险 Dbnph1 基因型与氧化磷酸化和脂质清除的显著富集分别相关；与人类糖尿病肾病共享的分子途径。因此，我们发现 FVB(db/db)小鼠重现了许多人类糖尿病肾病的临床、组织病理学和分子特征。在这些小鼠中确定潜在的易感基因和下游失调的途径可能有助于深入了解人类疾病的发病机制。
