Leehey D J, Singh A K, Alavi N, Singh R
Hines Veterans Affairs Hospital, Illinois 60141, USA.
Kidney Int Suppl. 2000 Sep;77:S93-8. doi: 10.1046/j.1523-1755.2000.07715.x.
Considerable evidence suggests that the intrarenal renin-angiotensin system plays an important role in diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) can attenuate progressive glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II action may decrease glomerular injury without altering glomerular pressures, it has been suggested that Ang II has direct effects on glomerular cells to induce sclerosis independent of its hemodynamic actions. To study nonhemodynamic effects of Ang II on matrix metabolism, many investigators have used cell culture systems. Glucose and Ang II have been shown to produce similar effects on renal cells in culture. For instance, incubation of mesangial cells in high-glucose media or in the presence of Ang II stimulates matrix protein synthesis and inhibits degradative enzyme (e.g., collagenase, plasmin) activity. Glucose and Ang II also can inhibit proximal tubule proteinases. Glucose increases expression of the angiotensinogen gene in proximal tubule cells and Ang II production in primary mesangial cell culture, which indicates that high glucose itself can activate the renin-angiotensin system. The effects of glucose and Ang II on mesangial matrix metabolism may be mediated by transforming growth factor-beta (TGF-beta). Exposure of mesangial cells to glucose or Ang II increases TGF-beta expression and secretion. Their effects on matrix metabolism can be blocked by anti-TGF-beta antibody or ARBs such as losartan, which also prevents the glucose-induced increment in TGF-beta secretion. Taken together, these findings support the hypothesis that the high-glucose milieu of diabetes increases Ang II production by renal, and especially, mesangial cells, which results in stimulation of TGF-beta secretion, leading to increased synthesis and decreased degradation of matrix proteins, thus producing matrix accumulation. This may be an important mechanism linking hyperglycemia and Ang II in the pathogenesis of diabetic nephropathy.
大量证据表明，肾内肾素 - 血管紧张素系统在糖尿病肾病中起重要作用。血管紧张素转换酶（ACE）抑制剂和血管紧张素II（Ang II）受体阻滞剂（ARBs）可在疾病模型中减轻进行性肾小球硬化，并能减缓人类疾病的进展。由于干扰Ang II作用的药物可能在不改变肾小球压力的情况下减少肾小球损伤，因此有人提出Ang II对肾小球细胞有直接作用，可独立于其血流动力学作用诱导硬化。为了研究Ang II对基质代谢的非血流动力学作用，许多研究人员使用了细胞培养系统。已证明葡萄糖和Ang II对培养的肾细胞产生相似的作用。例如，在高糖培养基中或在Ang II存在下培养系膜细胞会刺激基质蛋白合成并抑制降解酶（如胶原酶、纤溶酶）的活性。葡萄糖和Ang II也可抑制近端小管蛋白酶。葡萄糖增加近端小管细胞中血管紧张素原基因的表达以及原代系膜细胞培养中Ang II的产生，这表明高糖本身可激活肾素 - 血管紧张素系统。葡萄糖和Ang II对系膜基质代谢的影响可能由转化生长因子 - β（TGF - β）介导。将系膜细胞暴露于葡萄糖或Ang II会增加TGF - β的表达和分泌。它们对基质代谢的影响可被抗TGF - β抗体或ARBs（如氯沙坦）阻断，氯沙坦还可防止葡萄糖诱导的TGF - β分泌增加。综上所述，这些发现支持以下假设：糖尿病的高糖环境会增加肾脏尤其是系膜细胞的Ang II产生，这会导致TGF - β分泌增加，进而导致基质蛋白合成增加和降解减少，从而产生基质积聚。这可能是糖尿病肾病发病机制中连接高血糖和Ang II的重要机制。
