Ricci Carlo, Iacobini Carla, Oddi Giovanna, Amadio Lorena, Menini Stefano, Rastaldi Maria Pia, Frasheri Aurora, Pricci Flavia, Pugliese Francesco, Pugliese Giuseppe
Department of Clinical Sciences, La Sapienza University, Rome, Italy.
Nephrol Dial Transplant. 2006 Jun;21(6):1514-24. doi: 10.1093/ndt/gfk089. Epub 2006 Jan 31.
GLUT1 upregulation and increased glucose transport activity may contribute to extracellullar matrix (ECM) accumulation characterizing diabetic nephropathy (DN). Rats of the Milan hypertensive strain (MHS) are resistant to both hypertensive and diabetic renal disease, due to a haemodynamic protection. On the contrary, those of the Milan normotensive strain (MNS) develop spontaneous glomerulosclerosis, and when rendered diabetic, show typical morphological and haemodynamic changes.
To assess whether susceptibility to diabetic glomerulopathy in MNS rats is associated with higher glucose transporter 1 (GLUT1) expression (and glucose transport activity) vs MHS rats, diabetic and nondiabetic MNS and MHS rats were followed for 6 months and mesangial cells derived from these animals were exposed to high glucose (HG) vs normal glucose (NG) conditions.
Glomerular expression of GLUT1 protein and ECM and transforming growth factor-beta (TGF-beta) mRNA was significantly upregulated in diabetic vs nondiabetic MNS, but not MHS rats. Upon exposure to HG and/or TGF-beta, mesangial cells from 1- and 8-month-old MNS rats showed higher glucose transport activity and GLUT1 membrane expression than those from age-matched MHS rats. Likewise, ECM and TGF-beta production increased more markedly in response to HG and/or TGF-beta in MNS vs MHS mesangial cells.
These data indicate that susceptibility to diabetic glomerulopathy in MNS rats is associated with increased GLUT1-dependent glucose transport activity in response to hyperglycaemia and/or TGF-beta, which may amplify ECM overproduction. Conversely, the haemodynamic protection from glomerulosclerosis in MHS rats is associated with lack of upregulation of TGF-beta/GLUT1 axis, thus supporting the concept that this axis may represent the link between haemodynamic and metabolic mechanisms of injury.
葡萄糖转运蛋白1（GLUT1）上调及葡萄糖转运活性增加可能导致糖尿病肾病（DN）所特有的细胞外基质（ECM）积聚。米兰高血压大鼠品系（MHS）对高血压和糖尿病肾病均有抗性，这归因于一种血流动力学保护作用。相反，米兰正常血压大鼠品系（MNS）会发生自发性肾小球硬化，并且在患糖尿病时会出现典型的形态学和血流动力学变化。
为评估MNS大鼠对糖尿病性肾小球病的易感性是否与葡萄糖转运蛋白1（GLUT1）的较高表达（及葡萄糖转运活性）有关（相对于MHS大鼠），对糖尿病和非糖尿病的MNS及MHS大鼠进行了6个月的跟踪观察，并将源自这些动物的系膜细胞置于高糖（HG）与正常血糖（NG）条件下。
与非糖尿病MNS大鼠相比，糖尿病MNS大鼠的肾小球GLUT1蛋白表达、ECM及转化生长因子-β（TGF-β）mRNA显著上调，但MHS大鼠未出现这种情况。在暴露于HG和/或TGF-β时，1月龄和8月龄MNS大鼠的系膜细胞比年龄匹配的MHS大鼠的系膜细胞表现出更高的葡萄糖转运活性和GLUT1膜表达。同样，与MHS系膜细胞相比，MNS系膜细胞对HG和/或TGF-β的反应中，ECM和TGF-β产生的增加更为明显。
这些数据表明，MNS大鼠对糖尿病性肾小球病的易感性与高血糖和/或TGF-β刺激下GLUT1依赖性葡萄糖转运活性增加有关，这可能会加剧ECM的过度产生。相反，MHS大鼠对肾小球硬化的血流动力学保护与TGF-β/GLUT1轴未上调有关，从而支持了这一轴可能代表损伤的血流动力学和代谢机制之间联系的概念。
