GLUT-1 overexpression - Link between hemodynamic and metabolic factors in glomerular injury?
GLUT-1 overexpression - Link between hemodynamic and metabolic factors in glomerular injury?
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DOI：
10.1161/01.hyp.0000075949.19968.ef
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发表时间：
2003-07-01
期刊：
影响因子：
8.3
通讯作者：
Gruden, G
中科院分区：
文献类型：
--
作者：
Gnudi, L;Viberti, G;Gruden, G
系膜基质沉积是高血压和糖尿病肾小球病变的标志。在相似的系统性高血压水平下，Dahl盐敏感但非自发性高血压大鼠（SHR）发生肾小球高血压，伴有转化生长因子β（1）（TGF-β（1））上调、系膜基质扩张和硬化。GLUT-1广泛表达，是系膜细胞中主要的葡萄糖转运蛋白。在体外肾小球系膜细胞中，GLUT-1过表达增加了基础葡萄糖转运，导致过量的纤连蛋白和胶原蛋白产生。TGF-β（1）已显示上调GLUT-1表达。我们证明，在高血压达尔盐敏感（S）大鼠中，喂食4%氯化钠（收缩压[SBP]：236+/-9 mm Hg），但在高血压相似的SHR中没有（SBP：230+/-10 mm Hg）或血压正常者（Dahl S喂食0.5%NaCl，SBP：145+/-5mmHg; Wistar-Kyoto，SBP：137+/-3mmHg），肾小球GLUT-1蛋白表达上调80%（P <0.03）。与DSN大鼠相比，DSH大鼠肾小球TGF-β 1蛋白表达上调2.7倍（P=0.02）。TGF-β 1的表达没有上调，在Wistar-Kyoto和SHR大鼠的肾小球中没有差异。作为肾小球高血压引起的体内血流动力学应激的体外替代物，我们使用了人和大鼠系膜细胞的机械拉伸。我们发现，在拉伸33小时后，肾小球系膜细胞过度表达GLUT-1（40%），基础葡萄糖转运也表现出类似幅度的增加（P均小于或等于0.01），这可以被抗TGF-β 1中和抗体阻断。这些研究表明，血液动力学和代谢因素之间存在一种新的联系，可能在肾小球高血压的条件下协同诱导进行性肾小球损伤。
Mesangial matrix deposition is the hallmark of hypertensive and diabetic glomerulopathy. At similar levels of systemic hypertension, Dahl salt-sensitive but not spontaneously hypertensive rats (SHR) develop glomerular hypertension, which is accompanied by upregulation of transforming growth factor beta(1) (TGF-beta(1)), mesangial matrix expansion, and sclerosis. GLUT-1 is ubiquitously expressed and is the predominant glucose transporter in mesangial cells. In mesangial cells in vitro, GLUT-1 overexpression increases basal glucose transport, resulting in excess fibronectin and collagen production. TGF-beta(1) has been shown to upregulate GLUT-1 expression. We demonstrated that in hypertensive Dahl salt-sensitive (S) rats fed 4% NaCl (systolic blood pressure [SBP]: 236+/-9 mm Hg), but not in similarly hypertensive SHR (SBP: 230+/-10 mm Hg) or their normotensive counterparts (Dahl S fed 0.5% NaCl, SBP: 145+/-5 mm Hg; and Wistar-Kyoto, SBP: 137+/-3 mm Hg), there was an 80% upregulation of glomerular GLUT-1 protein expression (Pless than or equal to0.03). This was accompanied by a 2.7-fold upregulation of TGF-beta(1) protein expression in glomeruli of DSH compared with DSN rats (P=0.02). TGF-beta(1) expression was not upregulated and did not differ in the glomeruli of Wistar-Kyoto and SHR rats. As an in vitro surrogate of the in vivo hemodynamic stress imposed by glomerular hypertension, we used mechanical stretching of human and rat mesangial cells. We found that after 33 hours of stretching, mesangial cells overexpressed GLUT-1 (40%) and showed an increase in basal glucose transport of similar magnitude (both Pless than or equal to0.01), which could be blocked with an anti TGF-beta(1)-neutralizing antibody. These studies suggest a novel link between hemodynamic and metabolic factors that may cooperate in inducing progressive glomerular injury in conditions characterized by glomerular hypertension.