Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice
Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice
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DOI：
10.1152/ajprenal.00021.2010
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发表时间：
2010-07-01
影响因子：
4.2
通讯作者：
Brosius, Frank C., III
中科院分区：
文献类型：
--
作者：
Zhang, Hongyu;Schin, MaryLee;Brosius, Frank C., III
Zhang H，Schin ML，Saha J，Burke K，Holzman LB，Filipiak W，Saunders T，Xiang M，Heilig CW，Brosius FC 3rd.足细胞特异性GLUT1过表达令人惊讶地减少小鼠糖尿病肾病系膜基质扩张美国肾脏生理学杂志299：F91-F98，2010年。首次发表于2010年4月7日; doi：10.1152/ajprenal.00021.2010. -促进性葡萄糖转运蛋白GLUT1表达增加导致类似糖尿病肾病的肾小球病，而预防GLUT1表达增加可延缓肾病。虽然许多GLUT1介导的作用可能是由于系膜细胞的作用，我们假设足细胞中GLUT1表达增加也有助于糖尿病肾病的进展。因此，我们在db/m C57 BLKS背景下产生了两个足细胞特异性GLUT 1转基因小鼠系（由podocin启动子驱动）。两个建立者的后代用于产生糖尿病db/db和对照db/m同窝小鼠。肾小球裂解物的免疫印迹显示，与野生型小鼠相比，转基因小鼠的GLUT1含量增加了3.5倍（线1）和2.1倍（线2）。与野生型小鼠相比，两种品系在24周龄时的空腹血糖和体重均显示出相似的增加。系膜指数（系膜簇中PAS阳性物质的百分比）在野生型糖尿病小鼠中增加88%（线1）和75%（线2），但在糖尿病转基因小鼠中仅增加48%（线1）和39%（线2）（P <0.05，转基因与野生型小鼠）。这种肾小球系膜扩张的减少伴随着纤连蛋白积累的减少，并且转基因糖尿病小鼠中血管内皮生长因子（VEGF）水平仅增加野生型糖尿病小鼠的一半。与野生型小鼠相比，转基因小鼠nephrin、neph1、CD2AP、podocin和GLUT4的水平没有显著差异。总之，糖尿病小鼠足细胞GLUT1表达增加不会导致早期糖尿病肾病;令人惊讶的是，它可能通过抑制足细胞VEGF增加来防止系膜扩张和纤连蛋白积聚。
Zhang H, Schin ML, Saha J, Burke K, Holzman LB, Filipiak W, Saunders T, Xiang M, Heilig CW, Brosius FC 3rd. Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice. Am J Physiol Renal Physiol 299: F91-F98, 2010. First published April 7, 2010; doi: 10.1152/ajprenal.00021.2010.-Increased expression of the facilitative glucose transporter, GLUT1, leads to glomerulopathy that resembles diabetic nephropathy, whereas prevention of enhanced GLUT1 expression retards nephropathy. While many of the GLUT1-mediated effects are likely due to mesangial cell effects, we hypothesized that increased GLUT1 expression in podocytes also contributes to the progression of diabetic nephropathy. Therefore, we generated two podocyte-specific GLUT1 transgenic mouse lines (driven by a podocin promoter) on a db/m C57BLKS background. Progeny of the two founders were used to generate diabetic db/db and control db/m littermate mice. Immunoblots of glomerular lysates showed that transgenic mice had a 3.5-fold (line 1) and 2.1-fold (line 2) increase in GLUT1 content compared with wild-type mice. Both lines showed similar increases in fasting blood glucose and body weights at 24 wk of age compared with wild-type mice. Mesangial index (percent PAS-positive material in the mesangial tuft) increased 88% (line 1) and 75% (line 2) in the wild-type diabetic mice but only 48% (line 1) and 39% (line 2) in the diabetic transgenic mice (P < 0.05, transgenic vs. wild-type mice). This reduction in mesangial expansion was accompanied by a reduction in fibronectin accumulation, and vascular endothelial growth factor (VEGF) levels increased only half as much in the transgenic diabetic mice as in wild-type diabetic mice. Levels of nephrin, neph1, CD2AP, podocin, and GLUT4 were not significantly different in transgenic compared with wild-type mice. Taken together, increased podocyte GLUT1 expression in diabetic mice does not contribute to early diabetic nephropathy; surprisingly, it protects against mesangial expansion and fibronectin accumulation possibly by blunting podocyte VEGF increases.