Benck Urs, Haeckel Sarah, Clorius John H, van der Woude Fokko J
V. Department of Medicine, University Hospital Mannheim, Mannheim, Germany.
Clin J Am Soc Nephrol. 2007 Jan;2(1):58-67. doi: 10.2215/CJN.02400706. Epub 2006 Dec 13.
Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with (99m)Tc-DTPA and (131)I-hippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.
血管紧张素转换酶抑制剂和血管紧张素II（AngII）1型受体阻滞剂可降低糖尿病肾病（DN）患者的蛋白尿水平并保护肾功能。其抗蛋白尿作用大于降压作用，这与肾小球滤过膜的筛滤特性有关。在DN中，硫酸乙酰肝素蛋白聚糖的肾小球染色减少。AngII抑制硫酸乙酰肝素的合成。此外，肝素可调节肾小球细胞中的AngII信号传导，抑制醛固酮合成并降低DN患者的蛋白尿。肝素的抗蛋白尿作用是否归因于其对肾素-血管紧张素-醛固酮系统的干扰？对10名患有DN和肾小球肾炎的志愿者以及对照组受试者在低剂量依诺肝素治疗前后进行了检查。用（99m）Tc-DTPA和（131）I-马尿酸盐清除率测定肾血流动力学。在正常盐摄入和限盐期间，于基线以及依诺肝素治疗前后输注AngII时测量肾小球滤过率（GFR）、有效肾血浆流量、平均动脉压和心率。依诺肝素未降低醛固酮水平。所有组的GFR均保持稳定。AngII导致有效肾血浆流量显著降低，而平均动脉压和心率显著升高。依诺肝素在正常盐摄入或限盐期间不影响AngII诱导的肾血流动力学变化。所有组在依诺肝素治疗前后对AngII的反应相同。在糖尿病患者中，依诺肝素使蛋白尿显著减少。得出的结论是，肝素在DN中的抗蛋白尿作用无法通过与肾素-血管紧张素-醛固酮系统的相互作用来解释。血流动力学无变化且蛋白尿减少表明肾小球滤过膜存在内在改变。这些作用仅在DN中可见，在肾小球肾炎中未见到。
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