内皮素受体 A 特异性刺激在链脲佐菌素诱导的糖尿病大鼠模型中的肾小球炎症和损伤。
Endothelin receptor A-specific stimulation of glomerular inflammation and injury in a streptozotocin-induced rat model of diabetes.
机构信息
Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30907-2500, USA.
出版信息
Diabetologia. 2011 Apr;54(4):979-88. doi: 10.1007/s00125-010-2021-4. Epub 2010 Dec 30.
AIMS/HYPOTHESIS: Activation of endothelin receptor-A (ET(A)) increases glomerular permeability to albumin (P(alb)) and elevates pro-inflammatory markers in hyperglycaemic rats.
METHODS
Male Sprague-Dawley rats were given streptozotocin (n = 32) or saline (sham; n = 32). Half of the animals in each group received the ET(A)-selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and P(alb) determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay.
RESULTS
At 3 and 6 weeks after streptozotocin injection, proteinuria was significantly increased compared with sham controls and significantly reduced by ABT-627 treatment. P(alb) was also increased at 3 and 6 weeks post-streptozotocin. ABT-627 had no effect on P(alb) or protein excretion in sham control rats. In glomeruli isolated from hyperglycaemic rats, incubation with BQ-123, a selective ET(A) antagonist, reduced P(alb), whereas BQ-788, a selective endothelin receptor-B antagonist had no effect (n = 6 rats per group, 5-8 glomeruli per rat). Glomerular and plasma content of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were significantly increased 6 weeks after streptozotocin (ELISA). ABT-627 attenuated these increases. After 6 weeks of hyperglycaemia, glomerular nephrin content was decreased with a concurrent increase in urinary nephrin excretion. ABT-627 prevented glomerular nephrin loss in hyperglycaemic rats (n = 5-8 rats per group; eight groups).
CONCLUSIONS/INTERPRETATION: These observations support the hypothesis that endothelin-1, via the ET(A) receptor, directly increases P(alb), possibly via nephrin loss, as well as early inflammation in the hyperglycaemic rat.
目的/假设：内皮素受体-A（ET(A)）的激活增加了高血糖大鼠肾小球对白蛋白的通透性（P(alb)）并升高了促炎标志物。
方法
雄性 Sprague-Dawley 大鼠给予链脲佐菌素（n = 32）或生理盐水（假手术；n = 32）。每组中的一半动物在高血糖确诊后立即接受内皮素 A 选择性拮抗剂 ABT-627（阿曲生坦；口服）治疗。通过筛分技术分离肾小球，并通过白蛋白渗透压梯度诱导的肾小球体积变化来测定 P(alb)。通过免疫荧光法评估肾小球足细胞层蛋白（nephrin）水平，通过免疫测定法测量尿足细胞层蛋白（nephrin）。
结果
在链脲佐菌素注射后 3 周和 6 周，与假手术对照组相比，蛋白尿显著增加，而 ABT-627 治疗显著减少。P(alb)在链脲佐菌素注射后 3 周和 6 周也增加。ABT-627 对假手术对照组的 P(alb)或蛋白排泄无影响。在高血糖大鼠分离的肾小球中，与选择性 ET(A)拮抗剂 BQ-123 孵育降低了 P(alb)，而选择性内皮素受体-B 拮抗剂 BQ-788 则没有影响（每组 6 只大鼠，每只大鼠 5-8 个肾小球）。链脲佐菌素注射后 6 周，肾小球和血浆可溶性细胞间黏附分子-1 和单核细胞趋化蛋白-1 的含量显著增加（ELISA）。ABT-627 减轻了这些增加。高血糖 6 周后，肾小球足细胞层蛋白含量减少，同时尿足细胞层蛋白排泄增加。ABT-627 防止了高血糖大鼠的肾小球足细胞层蛋白丢失（每组 5-8 只大鼠；8 组）。
结论/解释：这些观察结果支持了内皮素-1 通过 ET(A)受体直接增加 P(alb)的假说，可能是通过足细胞层蛋白丢失以及高血糖大鼠的早期炎症。
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