Department of Cardiology, Peking University People's Hospital, Beijing, China.
Chin Med J (Engl). 2011 Feb;124(4):562-7.
Diabetic nephropathy is a major cause of renal failure in diabetes mellitus (DM). It has been known that renin-angiotensin system (RAS) blockers have a renal protective effect. This study aimed to investigate whether treatment with angiotensin II receptor blocker, olmesartan, could modify renal hemodynamic variables and vascular structural properties, then attenuate renal injury in streptozotocin (STZ)-induced DM rats.
DM was induced in male Wistar rats by intraperitoneal administration of STZ. The rats were then randomized to a DM group and an olmesartan treatment (OLM + DM) group. The normal group (non-DM) were administered only citrate buffer. At the end of the 14th week, blood glucose, kidney weight/body weight and urinary protein-to-creatinine ratio were determined. Further, the flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated, perfused kidneys. From the relationship, 3 indices of vascular structural properties were estimated: slope of flow-pressure (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of pressure-GFR (glomerular filtration capacity against pressure) and threshold pressure for beginning filtration at pressure-GFR (preglomerular to postglomerular vascular resistance ratio). Kidneys were then perfusion fixed for histological analysis. The renal histopathology was observed by light microscopy.
The body weight of DM rats was lower than that of non-DM rats. Blood glucose, kidney weight/body weight, urinary protein-to-creatinine ratio were significantly greater in DM rats than in non-DM rats. The parameters such as kidney weight/body weight, urinary protein-to-creatinine ratio in OLM + DM rats had dramatically decreased compared with those in DM rats. However, the treatment with olmesartan had no effect on blood glucose levels. The slope of flow-pressure relationship was greater in DM rats than that in non-DM rats (P < 0.05). But the slope of the pressure-GFR relationship was lower in DM rats than that in non-DM rats (P < 0.05) with the x-intercept of the line similar between the two groups. The slope of the flow-pressure relationship was decreased in DM rats group treated with olmesartan (P < 0.05). Moreover, olmesartan significantly increased the slope of the pressure-GFR relationship in DM rats (P < 0.05). The x-intercept of the pressure-GFR relationship reduced following olmesartan in DM rats.
Treatment with olmesartan reduced urinary protein-to-creatinine ratio independent of blood glucose and increased average renal vessel lumen diameter in the perfused kidneys of STZ-induced DM rats, predominantly in preglomerular vessels, and then improved renal excretory capability. These findings were consistent with remodeling of the preglomerular vasculature in our hisological measurements.
糖尿病肾病是糖尿病（DM）患者肾衰竭的主要原因。已知肾素-血管紧张素系统（RAS）阻滞剂具有肾脏保护作用。本研究旨在探讨血管紧张素 II 受体阻滞剂奥美沙坦是否可以改变链脲佐菌素（STZ）诱导的 DM 大鼠的肾脏血流动力学变量和血管结构特性，从而减轻肾脏损伤。
雄性 Wistar 大鼠腹腔注射 STZ 诱导 DM。然后将大鼠随机分为 DM 组和奥美沙坦治疗（OLM+DM）组。正常组（非 DM）仅给予柠檬酸盐缓冲液。在第 14 周结束时，测定血糖、肾脏重量/体重和尿蛋白/肌酐比。进一步，为最大程度扩张的灌注肾脏确定流量-压力和压力-肾小球滤过率（GFR）关系。从该关系中，估计了 3 个血管结构特性指标：流量-压力斜率（最小肾血管阻力，反映肾小球前和肾小球后血管腔的整体尺寸）、压力-GFR 斜率（肾小球滤过能力与压力）和压力-GFR 开始过滤时的阈值压力（肾小球前到肾小球后血管阻力比）。然后将肾脏进行灌注固定用于组织学分析。通过光镜观察肾脏组织病理学变化。
DM 大鼠的体重低于非 DM 大鼠。DM 大鼠的血糖、肾脏重量/体重、尿蛋白/肌酐比均显著高于非 DM 大鼠。与 DM 大鼠相比，OLM+DM 大鼠的肾脏重量/体重、尿蛋白/肌酐比显著降低。然而，奥美沙坦治疗对血糖水平没有影响。DM 大鼠的流量-压力关系斜率大于非 DM 大鼠（P<0.05）。但是，DM 大鼠的压力-GFR 关系斜率低于非 DM 大鼠（P<0.05），两组的线的 x 截距相似。DM 大鼠的流量-压力关系斜率在用奥美沙坦治疗后降低（P<0.05）。此外，奥美沙坦显著增加了 DM 大鼠的压力-GFR 关系斜率（P<0.05）。DM 大鼠用奥美沙坦治疗后，压力-GFR 关系的 x 截距降低。
奥美沙坦治疗可降低尿蛋白/肌酐比，且独立于血糖，并增加 STZ 诱导的 DM 大鼠灌注肾脏的平均肾血管腔直径，主要在肾小球前血管中，从而改善肾脏排泄能力。这些发现与我们的组织学测量中肾小球前血管重塑一致。
