Hammad Samar M, Hazen-Martin Debra J, Sohn Mimi, Eldridge Leslie, Powell-Braxton Lyn, Won Wesley, Lyons Timothy J
Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston 29425, USA.
Kidney Blood Press Res. 2003;26(5-6):351-61. doi: 10.1159/000073942.
BACKGROUND/AIMS: The contribution of preexisting hypercholesterolemia to diabetic nephropathy remains unclear. We assessed the impact of hypercholesterolemia on diabetic nephropathy using a double knockout (DKO) mouse, null for the low-density lipoprotein receptor (LDLRNDASH;/NDASH;) and the apoB mRNA editing catalytic polypeptide 1 (APOBEC1NDASH;/NDASH;).
Wild-type (WT) and DKO mice received sham or streptozotocin injections at age 7 weeks, yielding control (WT-C, DKO-C) and diabetic (WT-D, DKO-D) groups. At sacrifice (age 40 weeks), albuminuria was determined by ELISA, and kidney sections were examined by light and electron microscopy.
Albuminuria increased in diabetic mice (WT-D: 82.4 +/- 37.2 microg/18 h; DKO-D: 58.0 +/- 45.7 microg/18 h) versusnondiabetic controls (WT-C: 10.2 +/- 7.2 microg/18 h; DKO-C: 8.6 +/- 5.3 microg/18 h) (p LT; 0.0001), but was unaffected by hypercholesterolemia. Light microscopy of kidney sections demonstrated increased collagen levels in glomeruli in WT-D mice, but not in DKO-D mice or either control group. Electron microscopy showed a thickened glomerular basement membrane in WT-D mice only. The proximal tubular basement membrane thickness was increased in both diabetic groups versusnondiabetic controls (p LT; 0.01); in WT-D mice this was attributable to collagen accumulation, but in DKO-D mice it was mainly caused by lipid vacuoles.
In this animal model, preexisting hypercholesterolemia did not exacerbate either glomerular lesions of diabetes (collagen accumulation, basement membrane thickening) or albuminuria, but appeared to mitigate these effects. Furthermore, the combination of hypercholesterolemia and diabetes resulted in a significant lipid accumulation in the tubular basement membrane.
背景/目的：既往存在的高胆固醇血症对糖尿病肾病的影响尚不清楚。我们使用低密度脂蛋白受体（LDLR−/−）和载脂蛋白B mRNA编辑催化多肽1（APOBEC1−/−）双敲除（DKO）小鼠评估了高胆固醇血症对糖尿病肾病的影响。
野生型（WT）和DKO小鼠在7周龄时接受假手术或链脲佐菌素注射，分为对照组（WT-C、DKO-C）和糖尿病组（WT-D、DKO-D）。处死时（40周龄），通过ELISA测定蛋白尿，并通过光镜和电镜检查肾脏切片。
与非糖尿病对照组（WT-C：10.2±7.2μg/18小时；DKO-C：8.6±5.3μg/18小时）相比，糖尿病小鼠（WT-D：82.4±37.2μg/18小时；DKO-D：58.0±45.7μg/18小时）蛋白尿增加（p＜0.0001），但不受高胆固醇血症影响。肾脏切片光镜检查显示，WT-D小鼠肾小球胶原水平增加，而DKO-D小鼠或任何对照组均未增加。电镜检查仅显示WT-D小鼠肾小球基底膜增厚。与非糖尿病对照组相比，两个糖尿病组近端肾小管基底膜厚度均增加（p＜0.01）；在WT-D小鼠中，这归因于胶原积累，但在DKO-D小鼠中，主要由脂质空泡引起。
在该动物模型中，既往存在的高胆固醇血症既未加重糖尿病的肾小球病变（胶原积累、基底膜增厚），也未加重蛋白尿，反而似乎减轻了这些影响。此外，高胆固醇血症与糖尿病的联合作用导致肾小管基底膜大量脂质积累。
