肾素-血管紧张素系统阻滞剂对单肾切除大鼠糖代谢异常的纠正

目的 有研究表明单肾切除大鼠会出现糖代谢异常且肾素-血管紧张素系统(renin-antiotensin system，RAS)激活是糖代谢异常的重要原因，而腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)是能量代谢总开关。因此，我们通过RAS阻滞剂对糖代谢和肾皮质中AMPK表达的影响来探讨RAS对异常糖代谢的致病作用及机制。方法 利用左肾切除大鼠模型，将40只大鼠随机平均分为单肾切除组 (uninephrectomy, UNX)、假手术组(sham)、血管紧张素转化酶抑制剂(angiotensin converting enzyme inhibitor, ACEI)和血管紧张素受体阻滞剂(angiotensin receptor blocker, ARB)治疗组。检测四组大鼠术后10个月的肾功能指标，包括空腹血尿素、血肌酐及尿总蛋白/肌酐比值；术后3, 6, 8和10个月的空腹血糖、血胰岛素，计算反映胰岛素抵抗的HOMA-IR (homeostasis model assessment-insulin resistance)。术后10个月，用蛋白免疫印迹法和免疫荧光法检测四组大鼠右肾皮质中AMPK的表达。结果 和sham组相比，UNX组大鼠在术后10个月出现血尿素、血肌酐和尿总蛋白/肌酐比值升高；3个月出现空腹胰岛素升高，8个月出现空腹血糖升高，3、10个月出现HOMA-IR升高；UNX大鼠残留肾中AMPK表达明显减少。ACEI或ARB几乎能纠正单肾切除引起的所有异常改变。结论 RAS阻滞剂通过恢复肾皮质AMPK的表达来纠正单肾切除引起的糖代谢异常，RAS阻滞剂和AMPK激活剂联合使用可能为临床肾功能不全伴糖代谢异常的患者提供新的治疗思路。

Renin-angiotensin system blockade in correction of glucose metabolic disturbance in uninephrectomized rats

Objective Studies have reported that uninephrectomized rats might develop disturbance of glucose metabolism induced by persistent intra-renin-angiotensin system (RAS) activation. Additionally, AMP-activated protein kinase (AMPK) is recognized as an energy sensor for energy homeostasis. Therefore, we research the pathogenic effects and underlying mechanisms of RAS on glucose dysmetabolism and AMPK expression in renal cortex with treatments of RAS blockade. Methods 40 rats were stratified into four groups: sham, uninephrectomy (UNX), UNX treated with angiotensin converting enzyme inhibitor Lisinopril (ACEI) and angiotensin receptors blockade Losartan (ARB) by using uninephrectomized rat model. Fasting blood samples were collected for measurements of renal function, reflected by fasting serum urea, creatinine and urinary total protein to creatinine ratio at 10 months post-uninephrectomy and glucose metabolism including fasting blood glucose, serum insulin and insulin resistance indicator-homeostasis model assessment (HOMA-IR) at 3, 6, 8 and 10 months. Lastly, expressions of AMPK from right kidneys were examined by western blot and immunofluorescence after 10 months. Results Compared with sham rats, uninephrectomized rats demonstrated high serum urea, creatinine and ratio of urinay total protein to creatinine. Hyperinsulinemia and hyperglycemia in uninephrectomized rats were obvious respectively at 3 and 8 months, while expression of AMPK from UNX group was significantly diminished. Importantly, treatment with ACEI or ARB could almost attenuate all of the abnormalities induced by uninephrectomy. Conclusion RAS blockade may ameliorate glucose metabolic disorders caused by uninephrectomy via restoring AMPK expression and combination use of RAS blockade and AMPK activator may provide a therapeutic target for patients with renal dysfunction accompanied with glucose dysmetabolism.