Influence of genetic background on albuminuria and kidney injury in Ins2+/C96Y (Akita) mice
Influence of genetic background on albuminuria and kidney injury in Ins2+/C96Y (Akita) mice
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DOI：
10.1152/ajprenal.90515.2008
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发表时间：
2010-03-01
影响因子：
4.2
通讯作者：
Coffman, Thomas M.
中科院分区：
文献类型：
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作者：
Gurley, Susan B.;Mach, Carrie L.;Coffman, Thomas M.
Gurley SB，Mach CL，Stegbauer J，Yang J，Snow KP，Hu A，Meyer TW，Coffman TM.遗传背景对Ins 2（+/C96 Y）（秋田）小鼠蛋白尿和肾损伤的影响美国肾脏生理学杂志298：F788-F795，2010年。首次发表于2009年12月30日; doi：10.1152/ajprenal.90515.2008。先前的研究已经表明，携带Ins 2（+/C96 Y）突变的秋田小鼠作为用于开发糖尿病肾病模型的I型糖尿病平台具有显著的优势（DN; Gurley SB，克莱尔SE，Snow KP，Hu A，Meyer TW，Coffman TM. Am J Physiol Renal Physiol 290：F214-F222，2006）。鉴于遗传因素在决定人类DN易感性中的关键作用，我们研究了遗传背景对秋田小鼠肾损伤的作用。为了产生一系列的近交系秋田小鼠品系，我们将Ins 2（C96 Y）突变回交到129/SvEv和DBA/2背景上超过六代，并将高血糖症和肾病的程度与标准C57 BL/6-Ins 2（+/C96 Y）品系进行比较。来自所有三个秋田品系的雄性小鼠均出现显著且相当的高血糖症。然而，在具有DBA/2 > 129/SvEv > C57 BL/6的等级的品系之间，蛋白尿水平存在显著差异。在所有品系中均观察到肾脏和肾小球肥大，但仅在129和C57 BL/6背景中观察到系膜基质与基线非糖尿病对照组相比显著增加。在F1（DBA/2 x C57 BL/6）-Ins 2（+/C96 Y）小鼠中，白蛋白尿的程度与亲本DBA/2-Ins 2（+/C96 Y）系相似;它们也发生了明显的超滤。这些研究确定了遗传背景对改变与Ins 2（C96 Y）突变相关的肾脏表型的强烈影响。这些自然发生的菌株差异的鉴定应证明是有用的肾病模型，并可能被利用，以允许识别新的易感性等位基因的糖尿病白蛋白尿。
Gurley SB, Mach CL, Stegbauer J, Yang J, Snow KP, Hu A, Meyer TW, Coffman TM. Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am J Physiol Renal Physiol 298: F788-F795, 2010. First published December 30, 2009; doi:10.1152/ajprenal.90515.2008.-Previous studies have shown that Akita mice bearing the Ins2(+/C96Y) mutation have significant advantages as a type I diabetes platform for developing models of diabetic nephropathy (DN; Gurley SB, Clare SE, Snow KP, Hu A, Meyer TW, Coffman TM. Am J Physiol Renal Physiol 290: F214-F222, 2006). In view of the critical role for genetic factors in determining susceptibility to DN in humans, we investigated the role of genetic background on kidney injury in Akita mice. To generate a series of inbred Akita mouse lines, we back-crossed the Ins2(C96Y) mutation more than six generations onto the 129/SvEv and DBA/2 backgrounds and compared the extent of hyperglycemia and renal disease with the standard C57BL/6-Ins2(+/C96Y) line. Male mice from all three Akita strains developed marked and equivalent hyperglycemia. However, there were significant differences in the level of albuminuria among the lines with a hierarchy of DBA/2 > 129/SvEv > C57BL/6. Renal and glomerular hypertrophy was seen in all of the lines, but significant increases in mesangial matrix compared with baseline nondiabetic controls were observed only in the 129 and C57BL/6 backgrounds. In F1(DBA/2 x C57BL/6)-Ins2(+/C96Y) mice, the extent of albuminuria was similar to the parental DBA/2-Ins2(+/C96Y) line; they also developed marked hyperfiltration. These studies identify strong effects of genetic background to modify the renal phenotype associated with the Ins2(C96Y) mutation. Identification of these naturally occurring strain differences should prove useful for nephropathy modeling and may be exploited to allow identification of novel susceptibility alleles for albuminuria in diabetes.