Kojima Naoki, Slaughter Tiffani N, Paige Adrienne, Kato Sota, Roman Richard J, Williams Jan M
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, USA ; Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Japan.
J Diabetes Metab. 2013 May 30;Suppl 9(5). doi: 10.4172/2155-6156.S9-005.
This study compared temporal changes in renal hemodynamics, proteinuria and the development of renal disease in Goto-Kakizaki (GK) type II diabetic rats that are resistant to the development of diabetic nephropathy and a genetically modified GK substrain (T2DN) carrying the mitochondrial genome and other alleles from Fawn hooded-hypertensive (FHH) rats is more susceptible to the development of renal injury. Both GK and T2DN rats were diabetic (>250 mg/ dL) and blood glucose levels were not significantly different at 3, 6 and 18 months of age. Blood pressure was also similar in both strains at all 3 ages. Renal blood flow (RBF) was 45% higher in 3 month old T2DN rats than GK rats but glomerular filtration rate (GFR) was similar. T2DN rats exhibited a progressive increase in proteinuria from 41 ± 2 to 524 ± 50 mg/day and 57% fall in GFR as they aged from 3 to 18 months of age. In contrast, proteinuria only increased to 162 ± 31 mg/day in GK rats and GFR remained unaltered. The kidneys from 18 month old T2DN rats exhibited severe glomerulosclerosis, interstitial fibrosis and tubular necrosis while kidneys from GK rats did not. Plasma creatinine levels were 2.4 fold higher in 18 month old T2DN than in GK rats. These data demonstrate that T2DN rats develop most of the features of diabetic nephropathy including progressive proteinuria and chronic kidney disease whereas the closely related GK strain does not, even though blood pressure and the level of hyperglycemia are similar.
本研究比较了对糖尿病肾病发展具有抗性的Goto-Kakizaki（GK）II型糖尿病大鼠以及携带来自黄褐毛高血压（FHH）大鼠线粒体基因组和其他等位基因的转基因GK亚系（T2DN）在肾脏血流动力学、蛋白尿和肾病发展方面的时间变化，T2DN对肾损伤的发展更敏感。GK和T2DN大鼠均患有糖尿病（血糖>250mg/dL），在3、6和18月龄时血糖水平无显著差异。在所有3个年龄段，两种品系的血压也相似。3月龄T2DN大鼠的肾血流量（RBF）比GK大鼠高45%，但肾小球滤过率（GFR）相似。随着T2DN大鼠从3月龄长到18月龄，蛋白尿从41±2mg/天逐渐增加到524±50mg/天，GFR下降了57%。相比之下，GK大鼠的蛋白尿仅增加到162±31mg/天，GFR保持不变。18月龄T2DN大鼠的肾脏出现严重的肾小球硬化、间质纤维化和肾小管坏死，而GK大鼠的肾脏则没有。18月龄T2DN大鼠的血浆肌酐水平比GK大鼠高2.4倍。这些数据表明，T2DN大鼠出现了糖尿病肾病的大多数特征，包括进行性蛋白尿和慢性肾病，而与之密切相关的GK品系则没有，尽管血压和高血糖水平相似。
